Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.[CH:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]3)=[N:15][C:6]2=[CH:5][CH:4]=1
Reactant: COCCCNc1nc(OC)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Yield: 76 %

Procedure:
6-Methoxy-N-(3-methoxypropyl)-3-nitropyridin-2-amine (33B) (1.56 mmol max, crude oil) and (R)-tert-butyl 3-formylpiperidine-1-carboxylate (1.56 mmol, 0.332 g) were added to an oven dried 50 mL round-bottomed flask equipped with a reflux condenser and for stirring under nitrogen. Ethanol (4 mL) and dimethyl sulfoxide (2 mL) were added and the solution was allowed to stir at room temperature for 5 min. Sodium hydrosulfite (4.68 mmol; 0.959 g of 85%) was then added and the resultant mixture was heated to reflux and allowed to stir for 16 hr. The reaction solution was then concentrated in-vacuo, poured into water (100 mL), extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording a brown oil that was further purified by silica gel chromatography (20% CH3CN/CH2Cl2) to afford tert-butyl 3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-1-carboxylate (33C) as a clear oil (1.19 mmol, 0.481 g, 76% yield over 2-steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 1.54-1.70 (m, 1H) 1.84 (dt, J=13.83, 2.81Hz, 1H) 2.02-2.21 (m, 4H) 2.73-2.88 (m, 1H) 2.96-3.18 (m, 2H) 3.29-3.41 (m, 5H) 3.98 (s, 3H) 4.08-4.44 (m, 4H) 6.65 (d, J=8.59 Hz, 1H) 7.86 (d, J=8.59 Hz, 1H). ESI-MS: m/z 405.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](O)=[O:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:16]([C:7]1[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)=[O:17]
Reactant: OCCNCCO
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N(CCO)CCO)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
3,5-bis-(1,1-dimetyletyl)-4-hydroxybenzenecarboxylic acid (2.5. g, 0.010 mol) and diethanolamine (1.05 g, 0.010 mol) were dissolved in 30 ml of dry dimethylformamide and dicyclohexylcarbodiimide (2.13 g, 0.0105 mol) in 10 ml of dry dimethylformamide was added over 5 minutes. After stirring overnight, the resulting colorless suspension was filtered, and the filtrate was evaporated, 3×25 ml of benzene was added and reevaporated to yield a white solid which was recrystallised from toluene.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:21])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:3]([CH3:21])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(C)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)nc3)c(C)cn2c1=O
Yield: 75.7 %

Procedure:
Methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-7,9-dimethyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-7,9-dimethyl-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.16 mmol) and 2-amino-pyridine-5-boronic acid pinacol ester (43 mg, 0.20 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 25:4) afforded the title compound as a yellow solid (44 mg, 69%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>C(O)C.CO.ClCCl>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=4)(=[O:17])=[O:16])=[CH:19][C:20]2=3)=[N:34]1
Reactant: Cn1nc(O)ccc1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2[C@@H]2O[C@@]21C
Solvent: CCO
Solvent: CO
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4cccc(O)c4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Yield: 48.7 %

Procedure:
(3S,4S)-6-(3-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (2.0 g) (see Preparation 15) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (1.5 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in ethanol (30 ml), pyridine (0.31 g) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 100 hours. After cooling the reaction was filtered and the filtrate was evaporated to yield a solid which was dissolved in 0.5% methanol/dichloromethane and filtered again. The filtrate was again evaporated and the residue was chromatographed on silica eluting with a solvent gradient of 0.5:99.5 to 3.75:96.25 methanol: dichloromethane to yield (3S ,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.0 g) as a white solid. Found: C,53.20; H,4.79; N,5.22. C23H24N2O7S, 0.75 CH2Cl2 requires C,53.00; H,4.79; N,5.10%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[C:15]3=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:19]([CH:16]1[CH2:17][CH2:18][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[C:15]1=[O:22])=[O:20]
Reactant: CN
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O
Product: CNC(=O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3d) from (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield: 17% of a colorless solid. MS: m/e=343.2 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K]>CN(C=O)C.C(OCC)C>[CH2:1]([N:9]1[C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]2[C:5]1=[O:15])[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3×50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5]([Cl:15])=[N:4][N:3]=1.[NH4+].[Cl-]>[Fe].CCO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5]([Cl:15])=[N:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)nnc(Cl)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(Cl)nnc(Cl)c2c1
Yield: 30.3 %

Procedure:
A mixture of 1,4-dichloro-6-nitro-phthalazine (1.24 g, 5.09 mmol), EtOH (20 mL), saturated aqueous NH4Cl (20 mL) and iron powder (1.42 g, 25.47 mmol) was heated to reflux for 4 h then concentrated. The residue was taken up in EtOAc washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (0.33 g, 30%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH:12]=[CH2:13])[N:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:3]3[C:2](=[O:1])[C:11]4[C:6]([O:5][C:4]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:7]([CH2:12][CH2:13][Cl:38])[N:8]=[CH:9][CH:10]=4)=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29]1.[ClH:38]
Reactant: C=Cc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CCCl)nccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 1-(4-(4-oxo-2-phenyl-8-vinyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (15 mg, 0.030 mmol) in DCM was added 4 M HCl in 1,4-dioxane (0.05 mL, 2 mmol). The reaction mixture was stirred at RT for 4 h. The solvents were removed in vacuo. The product was chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as an HCl salt (5 mg, 38%). 1H NMR (500 MHz, CD3OD): δ 8.61 (d, 1H), 7.95 (d, 1H), 7.51-7.30 (m, 9H), 4.15-4.08 (m, 2H), 3.68-3.60 (m, 2H), 2.75-2.67 (m, 2H), 2.55-2.42 (m, 2H), 2.28-2.12 (m, 1H), 1.98-1.88 (m, 1H). LCMS (Method I): RT=4.49 min, [M+2]+=432.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 193.8 %

Procedure:
To a solution of 1-benzyl-4-methyl-4-piperidinol (3.6 g, 17.5 mmol) in 75 mL of benzene was added AlCl3 (11.7 g, 87.7 mmol) in one portion at room temperature. After stirring at room temperature for 30 min, the reaction mixture was heated to reflux for 8 h. The red colored solution was allowed to cool and then poured over 100 g of ice-water. It was extracted with EtOAc (2×100 mL) and the organic layer was washed with solution of Rochelle's salt. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 1-benzyl-4-methyl-4-phenyl piperidine as a red oil (4.5 g, 97% yield). It was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O1CCOCC1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O[C@@H]1CCNC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
8 g (46 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene 1,80 ml of dioxane and 8.14 g (0.095 mol) of (R)-(+)-3-pyrrolidinol are respectively placed in the reactor. The mixture is refluxed for one hour. The reaction medium is poured into a mixture of water (100 ml)-ice (200 g). A yellow product precipitates. This product is filtered off, washed with water (3×30 ml) and then dried under vacuum at 45° C. 8.38 g (75%) of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2) are thus recovered.
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:45].[Na+]>CCO.O>[CH:1]1([S:6]([C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(SC6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)C6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of (5R)-3-{2-[4-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (276 mg) in EtOH (15 ml) and water (5 ml) was treated with sodium periodate (391 mg) and stirred at room temperature under nitrogen for 3 h. The solution was concentrated in vacuo before pouring into water and extracting with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound (278 mg). LCMS RT=3.42 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(C(C)C)C(C)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To the solution of dimethylamine (284 mg, 6.3 mmol, 1.5 equiv.) and DIPEA (1 mL) in DCM (15 mL) was added dropwise a solution of 4-nitrobenzene-1-sulfonyl chloride (800 mg, 4.2 mmol, 1.0 equiv.) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was washed with water and brine. The organic layers was dried (Na2SO4) and concentrated to get the residue, which was washed with isopropyl ether to afford compound N,N-dimethyl-4-nitrobenzenesulfonamide (879 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[O:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19].[I:27]Cl>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[F:1][C:2]1[CH:7]=[C:6]([I:27])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[O:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19]
Reactant: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCO2
Reactant: ClI
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: -50 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A stirred solution of 7-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-methyl-8-nitro-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (0.25 g, 0.66 mmol) in dry DCM (10 mL) and iodine monochloride (0.8 mL) were added to silver tetrafluoroborate (0.4 g, 2.05 mmol) in DCM (10 mL) previously degassed with nitrogen for 30 minutes at −50° C. The resulting mixture was stirred at −50° C. for 1 hour. The reaction was monitored by TLC (50% ethylacetate in hexane). This was followed by the addition of 20 mL of sodium thiosulphate and filtered through celite. The filtrate was concentrated to afford 0.2 g of the product (70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][C:5]([CH2:6][C@@H:7]([NH:32][CH:33]2[CH2:39][CH:38]3[N:40](C(OC(C)(C)C)=O)[CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1>Cl.C(OCC)C>[ClH:1].[CH:38]12[NH:40][CH:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]([NH:32][C@@H:7]([C:8]([N:10]1[CH:11]3[CH2:17][CH2:16][CH:15]1[CH2:14][CH:13]([N:18]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:12]3)=[O:9])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:49][CH:48]=1)[CH2:39]2
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.7 %

Procedure:
0.21 g of tert-butyl 3-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate is placed in 1.53 ml of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature overnight. Trituration, rinsing with diethyl ether, and filter-drying of the precipitate obtained are carried out. The crystals are then dried over P2O5 under reduced pressure. 0.12 g of N-[8-(N-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea hydrochloride is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:31].[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:33]1([CH3:38])[C:32]([C:30]([CH2:29][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]3)[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:31])=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Reactant: Cc1ccccc1C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.05 g) obtained from Step 1 of Referential Example 10 was dissolved in toluene (14 ml), 2-bromo-2′-methylacetophenone (723 mg), 1N aqueous sodium hydroxide (7 ml) and tetra n-butylammonium bromide (20 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was separated into organic layer and aqueous layer, the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=5:1), to thereby obtain 557 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:12][C@@H:11]3[CH2:13][C@H:8]2[C:9](=[O:14])[O:10]3)=[O:6])[CH2:4][CH2:3]1.Cl.[NH2:16][C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1.C(C(CCCC)C([O-])=O)C.[Na+].Cl.[Cl-].[Na+]>O.ClCCl>[C:20]([C:17]1([NH:16][C:9]([C@@H:8]2[CH2:13][C@H:11]([OH:10])[CH2:12][N:7]2[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:6])=[O:14])[CH2:19][CH2:18]1)#[N:21]
Reactant: N#CC1(N)CC1
Reactant: CC1(C(=O)N2C[C@@H]3C[C@H]2C(=O)O3)CC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)N2C[C@@H](O)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
(1S,4S)-5-(1-Methyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (100 g, 512 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (62.0 g, 523 mmol), and sodium 2-ethylhexanoate (97%, 96.5 g, 563 mmol) were dissolved in water (500 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, dichloromethane (500 mL) was added, the mixture was acidified by addition of hydrochloric acid (25% m/m, 13.8 mL, 106 mmol), and sodium chloride (120 g) was added. The mixture was stirred for 1 h, phases were separated, the aqueous layer was extracted with dichloromethane (3×330 mL) and the combined organic extracts were concentrated in vacuo to a volume of ca. 1.1 L. Ethyl acetate (1.1 L) was added, the mixture was concentrated in vacuo to a volume of ca. 1 L and heptane (1 L) was added within 30 min. The resulting suspension was stirred for 2 h at 2° C., filtered, the precipitate was washed with cold ethyl acetate/heptane 1:1 (v/v, 340 mL) and heptane (340 mL) and dried in vacuo to afford the title compound as light yellow crystals (129.4 g, 90%). MS (ESI & APCI): m/z=278.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ 0.60-0.65 (m, 2H), 0.89-0.92 (m, 1H), 0.95-0.98 (m, 1H), 1.20-1.26 (m, 2H), 1.33 (s, 3H), 1.50-1.57 (m, 2H), 2.13 (ddd, J=5.0 Hz, 9.0 Hz, 14.1 Hz, 1H), 2.39 (br d, J=14.3 Hz, 1H), 3.76 (dd, J=4.3 Hz, 11.6 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H), 4.48-4.53 (m, 1H), 4.57 (d, J=9.0 Hz, 1H), 4.70 (br s, 1H), 7.92 (br s, 1H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 59.9 %

Procedure:
1-Indanone (5.00 g, 37.8 mmol) was dissolved in sulfuric acid (40 mL), and thereto was added dropwise a solution of potassium nitrate (3.83 g, 37.8 mmol) in sulfuric acid (10 mL) under ice-cooling. The mixture was stirred for 1 hr under ice-cooling, ice was added to the reaction solution, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, and purified by silica gel column chromatography (ethyl acetate/hexane=15/85→45/55) to give the title compound (4.01 g, yield 60%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[N:11][CH:12]=[CH:13][C:18]=2[OH:19])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)Nc1ccc2c(O)ccnc2n1
Temperature: 250 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
5-((6-Acetamido-2-pyridylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.3 g, 4.3 mmol) was added in portions to a stirred mixture of biphenyl (13.3 ml) and phenyl ether (36.8 ml) heated at 250° C. and the resulting mixture was stirred for 1 hour at 250° C. The mixture was allowed to cool and was diluted with hexane. The precipitate was collected by filtration and dried to give 2-acetamido-5-hydroxy-1,8-naphthyridine (720 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=C(OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=[N:22]C=CC=1B(O)O>>[F:1][C:2]1[CH:7]=[N:22][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1ccncc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2ccncc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (3-fluoropyridin-4-yl)boronic acid gave the title compound.