Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1COCC1>[O:16]([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(CBr)C(=O)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(COc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of ethyl 2-bromomethylacrylate (2.00 g, 10.4 mmol, ref: Villieras, J. and Rambaud, M. Synthesis, 1982, 914) and phenol(975 mg, 1.0 eq) in dry THF (20 mL) under N2 at 0° C. was treated with anhydrous K2CO3 (1.43 g, 1.0 mol eq). No reaction was observed for 1 h. Anhydrous DMF (20 mL) was added and stirred for 2 h at 0° C. and for 1 h at room temperature. After evaporation of DMF, water(100 mL) was added, and the reaction was extracted with ethyl acetate (100 mL×2). The organic extract was washed with brine (100 mL), dried (anh. Na2SO4), filtered and concentrated. Flash chromatography (40% CH2Cl2/hexanes) gave 1.712 g (80%) of the title compound.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9]C(=O)C2C=CC=CC=2)[CH2:4]1)#[N:2].O(C)[Na]>CO>[OH:9][C@H:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4]1
Reactant: N#C[C@H]1CCC[C@H](OC(=O)c2ccccc2)C1
Agent: CO[Na]
Solvent: CO
Product: N#C[C@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of the above benzoic acid trans-3-cyano-cyclohexyl ester (0.29 g, 1.3 mmol) and 0.5M NaOCH3 (0.13 mL, 0.065 mmol) in MeOH (1 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using 3:2 hexanes:EtOAc as an eluent to afford 0.12 g (78%) of trans-3-hydroxy-cyclohexanecarbonitrile as a colorless oil.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](O)=[O:12])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([CH2:14][OH:15])=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(CO)c2ccccc12
Yield: 70 %

Procedure:
The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithium Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1N HCl. The product was extracted with ethyl acetate (3×), washed with aqueous sodium bicarbonate (3×), water, brine, and dried over magnesium sulfate. 1,4-Bishydroxymethylnaphthalene (70%) was obtained as a solid after evaporation of the solvent and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:15]2[CH:16]=[CH:17][C:12]([C:2]([F:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck flask [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.53 mmol, prepared in example 1), 3-aminobenzene boronic acid (188 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol) and tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol) were combined in dioxane/water (20 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (276 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate 1:1 to yield the title compound (164 mg, 90%) as a viscous oil. Ion spray M.S. 351.4 (M*+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1
Reactant: C=O
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCNCC2=O)CC1
Product: CN1CCN([C@H]2CC[C@H](C(=O)Nc3c(C(=O)Nc4ccc(Cl)cn4)oc4cccnc34)CC2)C(=O)C1

Procedure:
N-(5-Chloropyridin-2-yl)-3-({[trans-4-(2-oxopiperazin-1-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxamide (60 mg) obtained in Example 125 and 35% aqueous formaldehyde solution (19 μl) are treated in a similar manner to Example 120 to give the title compound (46 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(O)C>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:11]1[N:10]=[CH:9][C:8]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=2)=[CH:13][N:12]=1
Reactant: Cc1ncc(Br)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ncc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 7.95 g (75 mmol) of sodium carbonate in 15 ml of water was added to a mixture of 2.6 g (15 mmol) of 5-bromo-2-methylpyrimidine [Coll. Czech.Chem. Comm. 14 (1949), 223–235], of 4 g (21 mmol) of 4-(trifluoromethyl)benzeneboronic acid and of 0.52 g (0.45 mmol) of tetrakis(triphenylphosphine)palladium in a mixture of 50 ml of 1,2-dimethoxy-ethane and of 30 ml of ethanol. The reaction mixture was stirred at 80° C. for 2 hours; afterwards, it was concentrated by distilling off the major part of the organic solvents. Subsequently, the residue was extracted with 3 portions of tert.-butyl methyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and finally evaporated. The residue was chromatographed on silicagel with a mixture of dichloromethane/tert.-butyl methyl ether (9/1 vol./vol.) as eluent. 3 g of the title compound was obtained as greenish solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10 mmol) in N,N-dimethylformamide (10 ml) were added tert-butyl bromoacetate (1.95 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (50 g, dichloromethane eluant) to afford the product as a pale-yellow solid (2.22 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[N:23]=[C:24]([CH3:30])[N:25](C(C)(C)C)[C:4]=2[C:3]=1[CH3:31].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[N:23]=[C:24]([CH3:30])[NH:25][C:4]=2[C:3]=1[CH3:31]
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c2[nH]1

Procedure:
The material from Example 32 was diluted with toluene then combined with phosphorous oxychloride and heated at reflux overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with water, basified with ammonium hydroxide then extracted several times with methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 10-40% ethyl acetate in hexane to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[CH2:38][OH:39])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[CH2:38][OH:39])[CH2:29][CH2:30][CH2:31]1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: OCC1CNCCC1N1CCC1
Product: OC[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (4-azetidin-1-yl-piperidin-3-yl)-methanol in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compounds were separated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H][H]>CCO.[Pd].[C]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][NH:11][C:10]=2[N:9]=1
Reactant: COC(=O)CCCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 1-4 (630 mg, 2.58 mmol) and 10% Pd/carbon (95 mg) in EtOH (25 mL) was stirred under a balloon of hydrogen for 72 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70% ethyl acetate/hexanes) to give 1-5 as a colorless oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:7][CH:6]=1)C.Cl.C([O-])([O-])=O.[K+].[K+]>>[CH3:30][N:26]1[CH:27]=[CH:28][N:29]=[C:25]1[CH:12]1[C:13]2=[N:14][NH:15][C:16](=[O:24])[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]=32)[NH:23][CH:11]1[C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 8-(4-(Diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (50 mg, 0.11 mmol) and 2 ml of hydrochloric acid (3 N) was stirred at room temperature for 2 hr. The reaction mixture was neutralized by K2CO3 to pH=7 and then filtered, 29 mg of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde was obtained, yield 70%. LC-MS (ESI) m/z: 372 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]([C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: COc1ccc(-n2c(C(=O)OC(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(=O)OC(C)C)c(O)c(O)c2C(=O)N(C)C)cc1

Procedure:
A solution of isopropyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (8) (130 mg, 0.240 mmol) in methanol (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford isopropyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-035) (69 mg, 79%) as a white solid: m/z 363 (M+H)+ (ES+); 361 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.42 (s, 1H), 7.10-6.99 (m, 2H), 6.91-6.82 (m, 2H), 4.83 (sept., J=6.2 Hz, 1H), 3.77 (s, 3H), 2.83 (br s, 6H), 0.96 (d, J=6.2 Hz, 6H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=[O:14])=[CH:3][CH:2]=1.[OH-].[Na+]>CC(C)=O.O>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([NH:7][C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]nnc1Nc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(Nc2nn[nH]c2C(=O)O)cc1
Yield: 96.6 %

Procedure:
Hydrolysis of ethyl 4-(p-tolylamino)-1,2,3-triazole-5-carboxylate (4.5 g) with aqueous sodium hydroxide as described in example 1c, afforded 3.85 g (96%) of acid of mp (acetone-water) 144° C., (Found; C, 55.32; H, 4.86; N, 25.64; C10H10N4O2 requires; C, 55.04; H, 4.62; N, 25.77%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])([O-:3])=[O:2].C([BH3-])#N.[Na+].FC(F)(F)CO.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl>CO.O1CCCC1>[N+:1]([C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1CO
Reaction time: 24 h

Procedure:
10 Parts 2-(2-nitro-4-chlorophenoxy)benzaldehyde and 2.4 parts sodium cyanoborohydride is dissolved with stirring in a mixture of 22 parts of tetrahydrofuran, 20 parts methanol and 10 parts by volume 2,2,2-trifluoroethanol. To the resulting mixture is added a trace of methyl orange and a sufficient amount of 2 N hydrochloric acid in methanol to attain a deep red color. Stirring is continued for approximately 24 hours at which time the solvents are removed in vacuo. The red, oily residue is dissolved in water and ethyl ether, and the ether layer separated. The water layer is extracted three times with 18 parts portions of ethyl ether. The ether extracts are combined with the ether layer, and extracted once with 50 parts of water. The ether is removed in vacuo to give crude 2-(2-nitro-4-chlorophenoxy)benzyl alcohol which is purified by chromatography.
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:29])[C:8]([C:24]([O:26]CC)=[O:25])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([O:20]C)[C:17]([F:22])=[CH:16][C:15]=2[F:23])=[CH:5][C:4]=1[F:30]>C(O)(=O)C>[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:29])[C:8]([C:24]([OH:26])=[O:25])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([OH:20])[C:17]([F:22])=[CH:16][C:15]=2[F:23])=[CH:5][C:4]=1[F:30]
Reactant: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2F)c2c(C)c(N)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: Cc1c(N)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c12
Reaction time: 48 h
Yield: 28.7 %

Procedure:
48% hydrobromic acid (3 ml) and acetic acid (2 ml) were added to ethyl 7-amino-1-(2,4-difluoro-5-methoxyphenyl)-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (420 mg), and the mixture was stirred for 2 days while heating under reflux. After the reaction mixture was allowed to cool, solids deposited were collected by filtration. The solids were washed with water, ethanol and diethyl ether in that order and dried to obtain the title compound (108 mg) as a pale brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][S:41]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)(=[O:43])=[O:42].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([CH2:52][CH2:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[NH:44][S:41]([CH3:40])(=[O:43])=[O:42])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(C)(=O)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (86 mg, 0.35 mmol) and 1-hydroxy-7-azabenzotriazole (48 mg, 0.35 mmol) in N,N-dimethylformamide (1.5 ml) and dichloromethane (1.8 ml) was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (68 mg, 0.35 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (155 mg, 0.35 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.06 ml, 0.35 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane (2:1), as eluent, to give 174 mg of ((3E)-4-(N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4](Cl)[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.Cl.[OH-:22].[Na+]>>[Cl:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: COc1ccc(Cn2cnc3c2C(Cl)NC(Cl)=N3)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(Cn2cnc3nc(Cl)[nH]c(=O)c32)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To the 2,6-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-1H-purine 6 (10 g, 32.46 mmol) was added NaOH (1 M, 100 ml). The reaction was stirred at 90° C. for 90 minutes. The reaction mixture was cooled to room temperature and then was neutralized by HCl (2 M) to pH 7. The desired product was precipitated out and was collected by filtration. The solid was air dried and placed in oven over night at 80° C. to afford 2-chloro-7-(4-methoxybenzyl)-1H-purin-6(7H)-one 7.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH:9](Br)[CH:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]1[CH2:6][CH2:7]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:14]([N:13]1[CH:5]2[CH2:6][CH2:7][CH:8]1[CH:9]1[NH:1][CH:4]2[CH2:11][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=NC1CCC(Br)C2CCC1N2Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
3.44 grams of the azide (1.1A) obtained in Ex. 1.1 are dissolved in 26 ml of anhydrous THF. To this solution 2.96 grams of triphenylphosphine, dissolved in 10 ml of anhydrous THE are added. The mixture is heated at reflux for 5 hours. At the end it is cooled at room temperature and 0.5 ml of water are added. It is further heated at reflux for 14 hours and then cooled at room temperature. The precipitate is filtered under vacuum and washed with THF, suspended in 50 ml of a CH2Cl2/H2O (1/1 v/v) mixture and treated with a 10% by weight K2CO3 aqueous solution up to pH 8. The organic phase is separated, dehydrated with sodium sulphate, filtered and evaporated under vacuum. 2.13 g of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane are recovered. Yield: 91%. 1H-NMR (CDCl3) δ 1.45-1.55 (m, 2H); 1.80-1.90 (m, 4H); 2.00-2.15 (m, 2H); 2.78-2.88 (m, 2H); 3.02-3.12 (m, 2H); 3.31 (s, 2H); 7.20-7.45 (m, 5H). Anal, calc. for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C, 78.71; H, 8.80; N, 12.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:3]=1
Reactant: O=C(O)C=Cc1cc(Br)ccn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
3-(4-Bromo-pyridin-2-yl)-acrylic acid (6.3 g, 27.6 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (3.0 g, 30.4 mmol), HOBT (7.5 g, 55.3 mmol), EDAC (10.6 g, 55.3 mmol) and triethylamine (11.5 mL, 82.9 mmol) were added to N,N-dimethylformamide (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 2.4 g of the titled compound as a pale yellow solid.