Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-methoxyphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 267.2; HRMS: calcd for C18H18O2+H+, 267.13796; found (ESI, [M+H]+), 267.1386.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([NH2:48])[S:47][C:41]=2[CH2:40]1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:48][C:46]3[S:47][C:41]4[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=4[N:45]=3)=[O:20])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN1CCc2nc(N)sc2C1
Reactant: N#Cc1ccc(N2CC[C@H](Oc3cccc(C(=O)O)c3)C2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCc2nc(NC(=O)c3cccc(O[C@H]4CCN(c5ccc(C#N)cc5)C4)c3)sc2C1
Reaction time: 1 h

Procedure:
Dissolve 3-[(S)-1-(4-cyano-phenyl)-pyrrolidin-3-yloxy]-benzoic acid (80.2 mg, 0.26 mmol), EDC (99.2 mg, 0.52 mmol) and HOBT (79.6 mg, 0.52 mmol) into 2 mL of DMF. The mixture is stirred for 1 h. Add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (46.5 mg, 0.28 mmol) to the mixture and place in a 60° C. bath with an Ar stream blowing over it. Stir mixture for 14 h resulting in a concentrated residue. LC-MS analysis indicates the desired product. Dissolve into 5 mL of DMF and purify via the Gilson Prep HPLC system (5%-80% CH3CN/H2O) to give 59.4 mg of the title compound, MS, electrospray 560.58 (M+H), rt 6.01 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][O:2][CH3:1]
Reactant: COC[C@@H]1CCCN1
Reactant: OCCBr
Product: COC[C@@H]1CCCN1CCO

Procedure:
Using an analogous procedure to those described in Note [39] immediately above, (2S)-2-methoxymethylpyrrolidine was reacted with 2-bromoethanol to give (2S)-1-(2-hydroxyethyl)-2-methoxymethylpyrrolidine; NMR Spectrum: (CDCl3) 1.5–1.65 (m, 1H), 1.65–1.8 (m, 2H), 1.8–2.0 (m, 2H), 2.3 (m, 1H), 2.6 (m, 1H), 2.8 (m, 1H), 2.95–3.05 (m, 1H), 3.17 (m, 1H), 3.3 (t, 1H), 3.35 (t, 1H), 3.37 (s, 3H), 3.5–3.7 (m, 2H).
Reaction SMILES: C(O)C.[CH3:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][C:17](/[CH:21]=[CH:22]/[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:31])[C:12]=3[N:32]=[C:9]2[CH2:8][O:7][CH2:6]1.C(Cl)(Cl)Cl>[Pd].CO.C(O)C>[CH3:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][C:17]([CH2:21][CH2:22][C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:31])[C:12]=3[N:32]=[C:9]2[CH2:8][O:7][CH2:6]1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(/C=C/C(=O)N5CCOCC5)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCC(=O)N5CCOCC5)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A 250-mL, glass Parr bottle was charged with palladium on carbon (10%, 0.05 g) and 2 mL of ethanol. A solution of (11S)-11-methyl-3-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (0.25 g, 0.63 mmol) dissolved in 125 mL of a 1:1 mixture of methanol/ethanol was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 50 PSI (3.4×105 Pa) overnight at ambient temperature. The reaction mixture was treated with additional palladium on carbon (10%, 0.05 g) and shaken under H2 at 50 PSI (3.4×105 Pa) for 3 days. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad rinsed with methanol and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 111 mg of the title compound as white crystals, mp 245-247° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.O>ClCCl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 47.5 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-methylphenyl)benzonitrile [MPB] 23 g, NBS 22 g and 2,2′-azobis(2,4-dimethylvaleronitrile) 47 mg was suspended in dichloromethane 44 ml and the mixture was stirred at 45-50° C. for about 5 hours. To the reaction mixture was added water 46 ml and the organic layer was separated. This operation was conducted three times. The organic layer was concentrated and acetonitrile 50 ml was added to the concentrate. The solution was again concentrated and acetonitrile 50 ml was added to the concentrate to give acetonitrile solution of 2-(4-bromomethylphenyl)benzonitrile [BMB] (116 g; Yield based on the theoretical amount of (2-(4-bromomethylphenyl)benzonitrile: 84%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17].[CH3:28]S(Cl)(=O)=O.C(N(CC)CC)C.CO>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:27][CH:25]([O:26][CH3:28])[C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(C2CO2)cc1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine(5 mmol) and 2-(4-nitro-phenyl)oxirane (5 mmol) was refluxed in 30 ml of isopropanol for 4 h. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was then washed with brine, the resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in dichloromethane (50 ml) and was added with methanesulfonyl chloride (2 eq.) and triethylamine (3 eq.) at 0° C. The reaction mixture was stirred at room temperature for 1 h. This solution was then concentrated on a rotary evaporator and dissolved in THF (50 ml), added triethylamine (3 eq.), followed by the addition of excess methanol (>10 eq.). After 12 hours stirring at 80° C., this solution is concentrated on a rotary evaporator and diluted with ethyl acetate. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexane=1:1). The resulting (4-fluoro-phenyl)-{1-[2-methoxy-2-(4-nitro-phenyl)-ethyl]-piperidin-4-yl}-methanone was dissolved in dichloromethane and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give (4-fluoro-phenyl)-{1-[2-methoxy-2-(4-nitro-phenyl)-ethyl]-piperidin-4-yl}-methanone; hydrochloride
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]2.Br[CH2:21][CH2:22]Br.Cl>>[CH2:21]1[CH2:22][O:2][C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]3)=[CH:10][C:11]=2[O:12]1
Reactant: BrCCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(O)cc2C1
Agent: Br
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)OCCO3

Procedure:
5,6-Dihydroxy-2-(di-n-propylamino)indan hydrobromide (200 mg, 0.6 mmol) was reacted with 1,2-dibromoethane (0.05 mL, 0.66 mmol) under the same reaction conditions as Example 4. The crude material was chromatographed (200 g silica gel) eluting with methylene chloride/methanol (9:1) to yield an oil. The oil was converted into the HCl salt and recrystallized using methanol/ethyl acetate/ether: mp 210°-215° C.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][C:25]=1[Cl:26])#[CH:18]
Reactant: C#Cc1cc(N)ccc1Cl
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.4 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 24 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-chloroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.67 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 24 h. It was poured into water (300 mL) and the residue washed down with MeOH. The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×25 mL); ethyl acetate/petroleum ether (1:10) (4×25 mL) and dried to give N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (209) (3.0 g, 100%) as a pale brown solid, mp 218-222° C.; 1H NMR δ [(CD3)2SO] 10.13 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 8.32-8.22 (m, 2H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 4.60 (s, 1H). Anal. Calcd for C15H8ClFN4.0.5H2O.0.5MeOH: C, 57.51; H, 3.43; N, 17.31. Found C, 57.33; H, 3.13; N, 17.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].[NH2:12][CH2:13][CH2:14][OH:15]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc(C2CO2)ccc1Br
Reactant: NCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCNCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) in THF (11 ml) was added 2-aminoethanol (13.2 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(4-bromo-3-fluoro-phenyl)-2-(2-hydroxy-ethylamino)-ethanol (5.37 g) as a yellow viscous oil which was used in the next step without further purification. MS (ISP): 280.2 ([{81Br}M+H]+), 278.1 ([{79Br}M+H]+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([F:5])=[CH2:4].[F:8]C(F)(F)C(F)C>>[FH:1].[F:1][C:2]([F:7])([F:6])[CH:3]([F:5])[CH2:4][F:8]
Reactant: C=C(F)C(F)(F)F
Reactant: CC(F)C(F)(F)F
Product: F
Product: FCC(F)C(F)(F)F

Procedure:
In one embodiment, 1,1,1,2,3-pentafluoropropane is prepared by hydrogenation of 1,1,1,2,3-pentafluoro-2-propene. In another embodiment, 1,1,1,2,3-pentafluoropropene is prepared by hydrogenation of 1,1,1,2,3-pentafluoro-2,3,3-trichloropropane (CFC-215bb). In some embodiments, hydrogen fluoride is produced as a by-product via the unintended dehydrofluorination of 1,1,1,2,3-pentafluoropropane over a hydrogenation catalyst, to produce 1,1,1,2-tetrafluoropropene and hydrogen fluoride. Under the hydrogenation conditions, 1,1,1,2-tetrafluoropropene is hydrogenated to 1,1,1,2-tetrafluoropropane. In some embodiments, hydrogen fluoride is produced as a by-product via the over hydrogenation of 1,1,1,2,3-pentafluoropropane which produces 1,1,1,2-tetrafluoropropane.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCN(c3ncccn3)CC2)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCN(c3ncccn3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (100 mg, 0.39 mmol) in methylene chloride (15 mL) was added 6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-ylamine (100 mg, 0.39 mmol) and diisopropylethylamine (0.35 mL, 1.90 mmol). To this solution was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP) in one portion (280 mg, 0.59 mmol). The mixture was stirred at room temperature overnight. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-yl]-amide as a light yellow powder. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C24H20F3N7O2 (m/e) 495, obsd 496 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([NH:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:22])=O>P(Cl)(Cl)(Cl)=O>[ClH:22].[Cl:22][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:21])([F:20])[F:19])[C:12]=1[N:11]=[C:9]1[NH:8][C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1]1
Reactant: N[C@@H]1CCCC[C@H]1NC(=O)Nc1c(Cl)cccc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: FC(F)(F)c1cccc(Cl)c1N=C1N[C@@H]2CCCC[C@H]2N1
Yield: 133 %

Procedure:
0.57 g of N-(trans-2-aminocyclohexyl)-N′-(2-chloro-6-trifluoromethylphenyl)urea in 20 ml of phosphorus oxychloride (POCl3) was boiled at reflux for 4–5 hours. The POCl3 was distilled off, water was added to the residue and the pH was adjusted to 7–8 using 2N NaOH. The mixture was then extracted with ethyl acetate, the organic solvent was distilled off and the residue was chromatographed on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. After removal of the eluent by distillation, the white solid residue was dissolved in a little ethyl acetate and acidified using a saturated solution of HCl gas in diethyl ether. Removal of the solvent by distillation and treatment of the residue with diisopropyl ether gave 0.4 g of the desired product as a solid of m.p. 160–165° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.[Mg].[C:19](=[O:21])=[O:20]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: Brc1ccc(OCCOC2CCCCO2)cc1
Reactant: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCOC2CCCCO2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 9.45 g (31.4 mmol) of 4-(2-tetrahydropyranyloxyethoxy)bromobenzene, 40 ml of dry tetrahydrofuran (THF) and 0.76 g (31.4 mmol) of magnesium metal is heated to boiling, and after about 15 minutes a spontaneous reaction ensues. The mixture is then maintained, with some external heating, at its boiling point and after 15 minutes 20 ml of THF is added. After an additional 15 minutes at boiling, a final 20 ml of THF is added, and boiling is continued until the total heating time is 2 hours. Most of the magnesium has disappeared at this point. The mixture is then cooled and carbon dioxide gas is introduced, at a slight positive pressure and with vigorous stirring, for 15 minutes. The mixture is filtered and rotoevaporated to remove the solvent. Ethyl acetate (150 ml), water (150 ml) and aqueous 3 N sulfuric acid (20 ml) are added to the residue. The aqueous layer is separated and extracted with ethyl acetate. The combined organic layers are washed with water (100 ml, 2X) and then with saturated aqueous sodium chloride and dried over calcium sulfate. Solvent is removed by rotoevaporation to give 4-(2-tetrahydropyranyloxyethoxy)benzoic acid.
Reaction SMILES: C([O:8][C:9](=[O:51])[CH2:10][N:11]([C:20](=[O:50])[C@H:21]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])[N:22]([N+:40]([O-])=O)[S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][C:30]([O:38][CH3:39])=[C:31]([O:36][CH3:37])[CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[N:22]#[N:40].[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:38][CH3:39])[CH:27]=[C:26]([S:23]([NH:22][C@H:21]([C:20]([N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][C:9]([OH:51])=[O:8])=[O:50])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])(=[O:25])=[O:24])[CH:35]=[CH:34]2
Reactant: [H][H]
Reactant: COc1cc2ccc(S(=O)(=O)N([C@@H](CCCNC(=N)N)C(=O)N(CCc3ccccc3)CC(=O)OCc3ccccc3)[N+](=O)[O-])cc2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CCc3ccccc3)CC(=O)O)cc2cc1OC
Product: N#N
Yield: 70 %

Procedure:
To a solution of 3.00 g of NG -nitro-N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.71 g (70%) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[CH3:14][CH2:15][O-].[Na+].[CH3:18]I.O>CCO.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH2:15][CH3:14])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CI
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCn1cc([N+](=O)[O-])cc1C(=O)OCC
Temperature: 80 °C
Yield: 77 %

Procedure:
4-Nitro-1H-pyrrole-2-carboxylic acid ethyl ester (5 g) was dissolved in 50 ml of dry EtOH, 50 ml of 1M sodium ethylate was added followed with 10 ml of CH3I. The reaction mixture was heated at 80° C. for 4 hours, cooled down to room temperature and distributed between water and chloroform. The organic phase was washed with water, dried with sodium sulfate and evaporated. The residue was recrystallized from hexane to yield 4.72 g (77%) of 1-propyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester 232.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O.C(Cl)Cl>[NH3:6].[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH3:18]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)CC1NCCc2ccccc21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)CC1c2ccccc2CCN1C
Product: N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 196.7 %

Procedure:
To a solution of material from Step 1 (6.71 g, 32.0 mmol) in 175 mL of dichloroethane was added 37% aqueous formaldehyde (22.6 mL, 300 mmol). After about 10 minute, sodium triacetoxyborohydride (31.2 g, 147.0 mmol) was added in 2 to 3 g portions with some cooling to maintain ambient temperature. The mixture was stirred for about 16 hours and DCM and water was added. The mixture was adjusted to pH 9–10 with 5N sodium hydroxide. The organic layer was separated, washed with brine, and then dried (Na2SO4) and concentrated in vacuo. Chromatography (silica gel, 5% (2N ammonia in methanol)/DCM) of the residue afforded about 6.9 g (96%) of the title compound. EIS-MS: 220 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.0 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 1.66 g of sodium hydride (60%, oil) and 100 ml of N,N-dimethylformamide was stirred at 50° C. for 30 minutes and then cooled to room temperature. To the reaction mixture was added 3.6 ml of methyl bromoacetate, after which the resulting mixture was stirred at the same temperature for 30 minutes and added to a mixed solvent of 200 ml of ethyl acetate and 200 ml of ice water, and the pH was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layer was washed with 50 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=10:1) to obtain 10.7 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate as a colorless oil.