Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.CN(C)C=O>ClCCl>[ClH:22].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1

Procedure:
A mixture of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid dihydrochloride (50 g), thionyl chloride (200 ml) and N,N-dimethylformamide (12.5 ml) was refluxed for 20 hours. After completion of reaction, the reaction mass was distilled out completely under vacuum to give residue which was diluted with dichloromethane (100 ml). Solid thus precipitated was filtered and washed to give 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride. To a mixture of 4-Methyl-N-(4-pyridin-3-yl-pyridin-2-yl)benzene-1,3-diamine (20 g) in dichloromethane (500 ml), potassium carbonate (80 g) was added and stirred for 30 minutes. 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (prepared above) was added to the reaction mass at 0-5° C. and refluxed for 10 hours. After completion of reaction, reaction mass was quenched with dilute hydrochloric acid (420 ml) up to pH 1.0-3.0 and layers were separated. Aqueous layer was washed with dichloromethane, diluted with tetrahydrofuran (120 ml) and basified up to pH 8.0-8.5 with 10% sodium hydroxide solution (200 ml). Solid thus precipitated was filtered, washed with sodium hydroxide solution and demineralised water to give title compound having amine intermediate: 39.7 ppm).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[F:12][C:13]([F:30])([F:29])[CH:14]1[CH2:16][N:15]1[S:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])(=[O:19])=[O:18]>C1COCC1>[CH3:28][C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([CH3:26])[C:20]=1[S:17]([NH:15][CH:14]([CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:13]([F:30])([F:12])[F:29])(=[O:18])=[O:19]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(CN2CCCc3cc(C)ccc32)C(F)(F)F)c(C)c1
Temperature: 130 °C

Procedure:
A mixture of 46 mg (0.31 mmol) of 6-methyl-1,2,3,4-tetrahydroquinoline and 91.5 mg (0.31 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1.5 mL of anhydrous THF was heated at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient) to afford 65 mg (47%), m.p. 143° C.-144° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:3]1=[O:28].CCN(C(C)C)C(C)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:14][CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:45])[C:3]1=[O:28]
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)C2CCOCC2)cc2ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCOCC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 1 h

Procedure:
To 1-methyl-3-({[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)quinolin-2(1H)-one (46.5 mg, 0.124 mmol) in CH2Cl2 (3 ml) and added DIEA (0.043 ml, 0.247 mmol) then cyclohexanecarbonyl chloride (0.018 ml, 0.136 mmol). The reaction was stirred for 1 hour and then concentrated in vacuo. Purified by reversed-phase chromatography (15-75% ACN in water (with 0.5 ml/l NH4OH), 20×100 mm Phenomenex Gemini C18 column). Desired fractions were concentrated in vacuo. HRMS [M+H]1+ 487.2962. 400 MHz 1H NMR (CDCl3) δ 7.59-7.47 (m, 2 H), 7.37 (d, J=8.52 Hz, 1 H), 7.33-7.13 (m, 7 H), 4.26 (d, J=18.4, 1 H), 4.17-3.95 (m, 2 H), 3.88-3.76 (m, 2 H), 3.74 (s, 3 H), 3.44-3.23 (m, 3 H), 2.97-2.91 (m, 0.8 H, rotational isomer A), 2.67-2.62 (m, 0.2 H, rotational isomer B), 2.42-2.19 (m, 0.2 H, rotational isomer B), 2.15-2.08 (m, 0.8 H, rotational isomer A), 1.95-0.95 (m, 15 H). 29.4 mg, 49%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br[C@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: C[C@@H](Br)C(=O)O
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in DCM (42 mL) and TEA (4.2 mL) was treated with (2R)-2-bromo-propionic acid (1.19 mL, 13.2 mmoles) and stirred overnight at 35° C. The DCM was removed under reduced pressure to provide crude title compound as a yellowish solid that was used in the next step. MS (APCI+) m/z 304 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]3[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Product: COc1ccc(COc2cc3c(cc2C(C)=O)C(C)(C)CCC3(C)C)cc1
Yield: 129.2 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl)-ethanone (0.315 g, 1.28 mmol) was alkylated with 4-methoxybenzylchloride (0.280 g, 1.79 mmol, 0.24 mL) as described in Example 21. Aqueous workup gave 1-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-ethanone 0.606 g (crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar—H), 7.39 (d of ABq, J=8.6 Hz, 2H), 6.92 (d of ABq, J=8.6 Hz, 2H), 6.91 (s, 1H, Ar—H), 5.06 (s, 2H, OCH2), 3.82 (s, 3H, OCH3), 2.55 (s, 3H, CH3), 1.67 (m, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31]CC4C=CC=CC=4)[CH:27]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].O1CCCC1>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1ccc(OC(=O)C2CCc3cc(OCc4ccccc4)ccc3C2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(OC(=O)C2CCc3cc(O)ccc3C2)cc1
Yield: 97.7 %

Procedure:
Then, 0.04 g of 5% palladium/carbon and 10 ml of a tetrahydrofuran solution containing 0.36 g of 2-(4-decyloxyphenyloxycarbonyl)-1,2,3,4-tetrahydro-6-benzyloxynaphthalene were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.29 g of 2-(4-decyloxyphenyloxycarbonyl)-1,2,3,4-tetrahydro-6-hydroxynaphthalene as a white crystal (isolated yield: 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CC(C)N
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Product: CC(C)NC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2
Yield: 99 %

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid was reacted with isopropylamine similarly to as described in example 2 with non-critical modifications to afford 166 mg (99%) 10-bromo-N3-isopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. 10-bromo-N3-isopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 43 mg (23%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-isopropyl-5,6,7,12-tetrahydro-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[CH:16]=[C:17](Br)Br.C([Li])CCC.[I:25]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16]#[C:17][I:25]
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C=C(Br)Br)c(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C)(C)[SiH2]Oc1ccc(C#CI)c(F)c1
Temperature: -70 °C
Yield: 96.2 %

Procedure:
To a solution of 26 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2,2-dibromoethylene in 50 ml of tetrahydrofurane were added dropwise 134 ml of n-butyl lithium (1.6M), while stirring at -70° C. After completion of the addition, the reaction solution was stirred for 3 hours, 10 ml tetrahydrofuran solution of 30 mmol of iodine were added dropwise and the solution was gradually elevated to room temperature. Afer completion of the agitation, the solution was poured into a sodium thiosulfate solution and extracted with heptane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown solid. Purification of the solid by a silica gel column chromatography gave 25 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2-iodoethyne as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 77.46 g (0.617 mol) of glycine methylester hydrochloride in CH2Cl2, 92 ml (0.66 mol) of triethylamine, a solution of 60 g (0.44 mol) of p-anisaldehyde in 50 ml of CH2Cl2 and 40 g of MgSO4 are successively added at 0–5° C. under N2 atmosphere. After stirring for 18 h at r.t. the reaction mixture is filtered through celite and washed with CH2Cl2. The filtrate is concentrated under reduced pressure and then the crude mixture is diluted with AcOEt. The AcOEt solution is filtered again to remove triethylamine hydrochloride and the filtrate diluted with toluene and concentrated under reduced pressure (azeotropic removal of H2O) to give 91.3 g of [(4-methoxy-benzylidene)-amino]-acetic acid methyl ester as light yellow crystals; NMR (C6D6): 3.18 (s, 3H), 3.34 (s, 3H), 4.13 (s, 3H), 6.69 (d, 2H, J=8.56 Hz), 7.70 (d, 2H, J=8.56 Hz), 7.79 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](#[N:18])[CH:16]=[CH2:17]>CO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:13][CH2:14]1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: C=CC#N
Solvent: CO
Product: Cc1cccc(C)c1N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
4-(2,6-Dimethylphenyl) piperazine (1 g, 5.23 mmol) in MeOH (10 ml) was cooled to 0° and 0.305 g (5.73 mmol) of acrilonitrile was added. The reaction was stirred overnight at room temperature and evaporated under vacuum affording 1 g of crude 3-[4-(2,6-dimethylphenyl)piperazin-1-yl]propionitrile as a waxy solid. This compound was dissolved in MeOH (60 ml), 2 ml 37% HCl and hydrogenated under pressure (40 psi) with 0.2 g of 10% Pd\C. The reaction was filtered and evaporated to dryness obtaining 1 g of the title compound, as a hydrochloride salt, that was used without further purification for the following reaction.
Reaction SMILES: [CH:1]12[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][NH:2]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20](O)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:2]2[CH2:3][CH2:4][NH:5][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:1]23)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CCC2NCCNC2C1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCCC21

Procedure:
The title compound of Example 15 base (0.49 g, 3.5 mmol) was coupled with 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol) as described in Example 5 to give the amide as a crystalline solid: mp 119°-120° C. (2-propanol); 1H-NMR (CDCl3) σ 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 4.48 (m, 1H), 3.66 (br s, 2H), 3.64 (m, 1H), 3.29 and 2.87 (m, 1H), 2.64-2.85 (complex m, 2H), 2.41 and 2.09 (m, 1H), 1.93-2.06 (complex m, 2H), 1.40-1.87 (complex m, 5H), 1.12-1.36 (complex m, 2H); Anal (calcd for C16H20Cl2 N2O): C 58.72, H 6.16, N 8.56. Found: C 58.80, H 6.17, N 8.52.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:13][CH3:14])[CH2:9][CH2:10][CH2:11]1
Reactant: COc1c(F)cccc1C1(O)CCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(F)cccc1C1CCC1
Yield: 78.9 %

Procedure:
To a 500 mL round-bottomed flask were added a stir bar, 1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.21 g, 26.6 mmol), dry DCM (250 mL), Et3SiH (39.0 mL, 244 mmol) and TFA (20 mL, 260 mmol). The resultant mixture was stirred at rt for 22 h before concentrating to dryness and subjecting the residue to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (3.78 g, 79%). 1H NMR (600 MHz, CDCl3) δ 7.03-6.99 (m, 1H), 6.99-6.95 (m, 1H), 6.91 (m, 1H), 3.86 (d, J=1.6, 3H), 3.83-3.72 (m, 1H), 2.39-2.28 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.98 (m, 1H), 1.89-1.80 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]([C:13]([OH:15])=O)[O:3]1.[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:13]([CH:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(c2ccccc2)C(C(=O)O)O1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: O=C1NC(c2ccccc2)C(C(=O)NCCO[N+](=O)[O-])O1
Yield: 7.5 %

Procedure:
Following a procedure similar to that described in Example 1, but using 112 mg of 2-oxo-4-phenyloxazolidine-5-carboxylic acid, 110 mg of N-(2-nitrooxyethyl)amine nitrate and 0.24 ml of diphenylphosphoryl azide, 12 mg of the title compound were obtained as colorless crystals, melting at 122°-124° C.
Reaction SMILES: Br[C:2]1[N:3]([C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=2[N:40]=1)[C@@H:4]1[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:5]1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:57]=[CH:58][C:59]([CH2:62][NH:63][C:2]3[N:3]([C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=4[N:40]=3)[C@@H:4]3[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[C@H:5]3[O:6][Si:7]([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8])=[CH:60][CH:61]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4cccc(OCc5ccccc5)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 83.3 %

Procedure:
A mixture of 8-bromo-2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)adenosine (0.660 g), 3′-benzyloxybiphenyl-4-ylmethylamine (0.832 g) and N,N-diisopropylethylamine (0.667 mL) in 1-propanol (9.6 mL) was heated under reflux with stirring for 62 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and 10% aqueous citric acid (10 mL). The organic layer was washed successively with 10% aqueous citric acid (10 mL×2), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.716 g).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)([O-:4])=[O:3].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH:12]=1)([O-:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1C1=CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (0.44 g, 1.8 mmol) was dissolved in a solution of pyridine (0.4 mL) and DCM (20 mL). Acetyl chloride (0.142 mL) was added and the mixture was stirred for 0.5 hours. The mixture was diluted with DCM (20 mL) and the organic solution washed with water then 1 N hydrochloric acid. The solution was dried with magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.4 g). LCMS m/z 247.4 [M+H]+. R.T.=3.70 min (Analytical Method 4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-n3cccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][NH2:27])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][NH:27][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:20][CH:19]=1
Reactant: NCc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCc2cccc(Oc3ccc(Cl)cc3)c2)c(Nc2cccnc2)c1=O
Yield: 84 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 3-(4-chlorophenoxy)-benzylamine.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:22]([O:24][CH2:25][CH3:26])=[CH2:23]>>[C:1]([O:4][CH2:5][CH:6]([O:9][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)CCl
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(C)OC(CCl)COC(C)=O
Reaction time: 2 h

Procedure:
To the crude acetate prepared in Example 8 was added 10 g of p-toluenesulfonic acid monohydrate and then dropwise, over a period of 2 hours, 815 g (11.3 moles) of ethyl vinyl ether. The reaction was midly exothermic and the temperature was maintained at 35°-37° C. by occasional cooling. After the addition was complete, the reaction mixture was heated at 35°-40° C. for 16 hours. The crude material was used in the subsequent step.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][NH:21][C@H:20]1[CH3:24])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[C@H:20]1[CH3:24])([CH3:18])[CH3:17]
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(C(F)(F)F)cc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 4-fluoro-5-methyl-2-(trifluoromethyl)benzonitrile (89 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (100 mg) and lithium carbonate (78 mg), the title compound was obtained as a colorless solid (yield: 17 mg) by an operation similar to that in Example 3.