Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CCCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CCCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 130 °C

Procedure:
6-Chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (289 mg, 991 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (425 mg, 1.98 mmol) were dissolved in N-methyl-2-pyrrolidinone (2 mL) and heated at 130° C. for 24 h. LCMS showed desired product mass, as well as starting material. A third equivalent of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate was added (213 mg, 0.991 mmol) and heating continued. After 8 h, a third portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.310 g) was added. After 24 h, the mixture was cooled and concentrated in vacuo (high vacuum, 100° C.) to a brown solid residue. Purification by chromatography (silica, 0 to 10% of a 9:1 MeOH:NH4OH solution in dichloromethane, 20 min) gave tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (271 mg, 577 μmol, 58%) as a light brown solid. LC-MS 470.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=O)[C@@H:9]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: C1CCOC1
Product: COc1cccc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (±)-cis tert-butyl 6-methoxy-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (1.4 g, 4.5 mmol) in 30 mL of THF at 0° C. was added borane THF complex (20 mL of a 1 M solution in THF, 20 mmol) dropwise. The reaction was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched carefully with water and extracted with ethyl acetate. The organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford 1.26 g (92%) of the title compound. 1H NMR (CDCl3) (some signals doubled due to rotamers): δ 6.68-6.55 (overlapping m, 3H), 4.42 (broad s, 1H), 3.95-3.82 (m, 1H), 3.78 (s, 3H), 3.64-3.55 (m, 1H), 3.38-3.15 (overlapping m, 4H), 3.02-2.92 (m, 1H), 2.52-2.42 (m, 1H), 3.63 and 3.61 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1.[CH3:24][O:25][CH2:26][C:27](Cl)=O.[OH-].[Na+]>C1COCC1>[Cl:14][C:13]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[C:15](=[O:16])[NH:17][C:27]([CH2:26][O:25][CH3:24])=[N:1][C:2]=3[N:7]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2Cl)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-chloro-[2,2′]bipyridinyl-5-carboxylic acid amide (0.5 g, 2.02 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add drop wise pyridine (0.36 g, 4.04 mmol) and methoxyacetyl chloride (0.48 g, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and reflux for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and dry under vacuum to give 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:24][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:18][CH2:19][C:20]([CH3:24])([OH:23])[CH2:21][CH2:22]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanone (764 mg, 2.5 mmol) in 80 mL of THF, cooled at −78° C., was added dropwise methylmagnesium chloride (3.5 mL, 3.0 M in THF, 10.5 mmol). The reaction mixture immediately turned bright yellow in color; it was then allowed to warm to RT. The reaction did not reach completion, so it was re-cooled to −78° C. and an additional aliquot of MeMgCl (3 mL, 9 mmol) was added. The resulting mixture was warmed to RT and then poured onto an aqueous solution of NH4Cl; it was extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (1-5/99-95 MeOH/CH2Cl2) to give: a less polar trans-isomer (130 mg, 16% yield, mp=193.0-195.4° C.; MS=325 (M+H)+), and the more polar cis-isomer (360 mg, 45% yield, mp=202.1-205.6° C.; MS=325 (M+H)+) as white crystalline solids.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[O:11][CH:10]1[C@H:30]([OH:62])[C@@H:31]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:54])[C@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:39]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:39][C@@H:38]([CH2:50][CH:51]([CH3:53])[CH3:52])[C:37]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C@@H:31]([C@H:30]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[O:11]1)[OH:62])[C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])=[O:54]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 65.4 %

Procedure:
tert-Butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (9 mg, 0.0099 mmol, obtained from Example 6) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (7 mg) under atmospheric pressure to provide tert-butyl (2S,3R)-2-[(3-{[(2S)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (5 mg, 65%) as a pale tan amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]2[C:11](=[O:18])[CH:12]([NH2:17])[CH2:13][CH:14]=[CH:15][CH2:16][CH:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[N:10]2[C:11](=[O:18])[C@@H:12]([NH:17][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:13][CH:14]=[CH:15][CH2:16][C@H:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCCC2CC=CCC(N)C(=O)N21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Reaction time: 0.08 h

Procedure:
A solution containing crude 7-amino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid methyl ester, 42, (50 mg, 0.2 mmol) and Et3N (0.56 mL, 4.0 mmol) in 5 mL THF is treated with excess benzoyl chloride (0.23 mL, 2.0 mmol) and stirred for 5 minutes. The reaction is quenched with MeOH and concentrated. The crude residue obtained is purified by preparative reverse phase HPLC (CH3CN/H2O) to yield 45 mg of desired product. 1H NMR (CDCl3) δ 7.92 (d, J=5.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 2H), 7.57–7.42 (m, 3H), 5.70 (m, 2H), 5.30 (m, 1H), 5.18 (m, 1H), 4.63 (m, 1H), 3.74 (s, 3H), 3.12 (m, 1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.29 (m, 2H), 1.90–1.60 (m, 5H); 13C NMR δ 172.8, 172.3, 166.4, 134.4, 131.8, 129.9, 128.8(2C), 127.3(2C), 125.0, 52.3, 51.8, 51.4, 50.8, 35.4, 34.2, 29.7, 26.4, 15.7.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:12]1([CH2:18][CH2:19][CH2:20][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1nc[nH]n1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCCn2cncn2)cc1
Reaction time: 12 h

Procedure:
A mixture of 14 parts by weight of 1,2,4-triazole, 200 parts by weight of acetonitrile, 32 parts by weight of potassium carbonate and 40 parts by weight of 3-phenylpropyl bromide is stirred for 12 hours. The mixture is then filtered and the filtrate is concentrated. Distillation gives 25 parts by weight of pure 1-(3-phenylpropyl)-1,2,4-triazole; b.p. (0.013 mbar): 114°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Br)nc1
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reaction time: 12 h
Yield: 71.8 %

Procedure:
To a suspension of 6-bromonicotinoyl chloride (0.5 g, 2.5 mmol) in dry chloroform (10 mL) was added 4-fluoroaniline (0.33 mL, 3.5 mmol) and 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, (0.85 g, 3.5 mmol). The mixture was stirred for 12 h, diluted with hexanes and the solids isolated by filtration. Purification by trituration using ethyl acetate/hexanes gave 0.53 g (73%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) a 10.51 (s, 1H), 8.87 (m, 1H), 8.20 (m, 1H), 7.82 (m, 1H), 7.74 (m, 2H), 7.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH:33]=[N:32][N:31]([CH3:34])[C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[CH:28]5[CH:33]=[N:32][N:31]([CH3:34])[CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: Cn1ncc2c(=O)[nH]c(CCl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5C(C=NN5C)C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 6-chloromethyl-1-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (66.4 mg, 87% yield). HRMS calculated for C24H28N6O4 464.5286. found (ESI, [M+H]+) 465.2256. 1H NMR (400 MHz, MeOD) δ ppm 1.70-1.93 (m, 4H) 2.09-2.31 (m, 2H) 2.53-2.66 (m, 1H) 2.80-2.91 (m, 1H) 2.93-3.02 (m, 1H) 3.10-3.21 (m, 1H) 3.33-3.43 (m, 2H) 3.48-3.57 (m, 2H) 3.65-3.75 (m, 1H) 3.83-3.90 (m, 6H) 4.37-4.51 (m, 2H) 6.97 (d, J=9.03 Hz, 2H) 7.83-7.91 (m, 1H) 7.97 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=2.77 min
Reaction SMILES: C([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[OH:24][C:25]1C(C)=CC(C#N)=CC=1OC>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[C:15]([CH3:23])=[CH:16][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[CH:18][C:3]=1[O:24][CH3:25])=[O:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: COc1cc(C#N)cc(C)c1O
Product: COc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is obtained as a reddish oil (1.3 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-3-methoxy-5-methyl-benzonitrile; LC-MS: tR=0.49 min, [M+H]+=327.98.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 78.2 %

Procedure:
4-Bromophenol (100 g, 0.587 mol) was dissolved in acetone (1100 ml), anhydrous potassium carbonate (159.53 g, 1.156 mmol) and benzyl bromide (103.78 g, 0.607 mol) were successively added thereto and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from hexane to give the title compound (120.76 g, 0.459 mol, 79%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].Br[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[CH2:14][CH2:13][C:5]1([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: COC(=O)C1CCCCC1=O
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CCC2OCCO2)CCCCC1=O

Procedure:
A solution of 2-carbomethoxycyclohexanone (2.0 g, 12.8 mmoles) in 50 mL of DMF was reacted at 70° C. for 15 h with 2-(2-bromoethyl)-1,3-dioxolane (4.6 g, 25 moles) and potassium carbonate (4.8 g, 34.8 mmoles). The reaction mixture was diluted to 500 mL with water and extracted with ethyl ether/ethyl acetate. The organic extracts were dried over sodium sulfate, and the solvent was evaporated to generate the title compound as an oil.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[N+:17]([C:14]1[CH:15]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=[CH:12][C:13]=1[OH:16])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
10 g of 4-nonylphenol (manufactured by Tokyo Kasei K.K., containing 10% of ortho compound) was dissolved in 30 ml of acetic acid and to the resulting solution was added 20 ml of 30% solution of nitric acid at 5°-10° C. for 2 hours. After 10 minutes, the resulting solution was treated with 50 g of ice water and then extracted with three 50-ml portions of ether. The ether was distilled off and then the residue was isolated using a silica gel column to obtain 9.33 g of the desired product in a 78% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>>[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:40]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOC(=O)c3ccccc3Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chloro-benzoyl chloride analogously to the procedure described in Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-[3-(2-chloro-benzoyloxy)-propyl]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 614.6, 616 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH3:15])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([C:10]3[CH:14]=[CH:13][O:12][CH:11]=3)[CH:7]=[CH:6][C:5]=2[CH3:15])=[O:30])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: CCNc1cc(-c2ccoc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCC(=O)O
Product: CCN(C(=O)CCCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccoc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-5-(furan-3-yl)-2-methylaniline was reacted with the 5-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-5-oxopentanoic acid obtained in Example 31-(i) to give 5-chloro-2-[(5-(ethyl[5-(furan-3-yl)-2-methylphenyl]amino)-5-oxopentanoyl)amino]benzoic acid.methyl ester (yield: 58%).
Reaction SMILES: C(OP([O-])OCC)C.C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([NH:35][C:36](=[O:38])[CH3:37])[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[CH:31](Br)[Br:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOC(C)=O>C1COCC1>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([NH:35][C:36](=[O:38])[CH3:37])[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[CH2:31][Br:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1ccc(C(=O)C(Br)Br)c(OCc2ccccc2)c1
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)CBr)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 118.9 %

Procedure:
A solution of diethylphosphite (12.6 μL, 13.5 mg, 97.6 μmol) and triethylamine (13.6 μL, 9.9 mg, 97.6 μmol) in THF (0.1 mL) was added to a stirred solution of N-[3-benzyloxy-4-(2,2-dibromo-acetyl)-phenyl]-acetamide (41 mg, 92.9 μmol) in THF (1.5 mL) at room temperature, and the reaction stirred for 2 hours. The mixture was poured into EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give N-[3-benzyloxy-4-(2-bromo-acetyl)-phenyl]-acetamide (40 mg, >100%), which was seen by NMR to be contaminated with a diethylphosphite-derived contaminant. The material could be used successfully in the following steps without further purification. All analytical data was as reported above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].CC(O)C>CCOCC.CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1ccc(C2(C#N)CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
A solution of 3.27 g (22.2 mmol) of (4-methoxyphenyl)acetonitrile and 4.93 g (24.4 mmol) of 1,3-dibromopropane in 15 mL of ether was added dropwise into 1.17 g (48.8 mmol) of NaH in 60 mL of DMSO. The temperature was held between 25° and 35° by water bath cooling. The mixture was stirred at room temperature for 18 hours. The mixture was cooled in ice water and 3 mL of 2-propanol was added dropwise, followed by the addition of 50 mL of water. The mixture was extracted with hexane (3×100 mL), and the combined extracts were washed with water (3×75 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 2.6 g (62%) product as colorless oil. 1H NMR (CDCl3) δ 2.01-2.14 (m, 1H), 2.35-2.50 (m, 1H), 2.55-2.66 (m, 2H), 2.77-2.87 (m, 2H), 3.83 (s, 3H), 6.94 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H). 13C NMR (CDCl3) δ 17.3, 35.1, 39.9, 55.6, 114.5, 124.9, 127.0, 132.1, 159.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16](O)=[O:17])[CH:10]=[CH:9]2)=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:3]([CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][OH:17])[CH:10]=[CH:9]2)[CH2:19][CH3:20])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2cc(C(=O)O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 6-(diethylaminocarbonyl)-2- naphthalenecarboxylic acid (18 g, 66 mmol) in THF (200 ml) was slowly added to a refluxing suspension of lithium aluminium hydride (7.5 g, 199 mmol) in THF (500 ml). The mixture was refluxed for an hour, then cooled at room temperature and treated with a mixture of THF (25 ml) and water (3.5 ml), with 20% sodium hydroxide (8.5 ml) and finally with water (33 ml). The white solid was filtered off and the solvent was removed under reduced pressure. Crude was dissolved in diethyl ether (200 ml) and extracted with 1N HCl (3×100 ml). The aqueous solution was treated with 32% sodium hydroxide and extracted with diethyl ether (3×100 ml). The organic solution was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 12.7 g (79% yield) of pure 6-(diethylaminomethyl)-2-naphthalenemethanol as thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:24][S:25]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:27])=[O:26]
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35° C. After 2 h, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield, containing also some of the corresponding bromo-compound, Caution: irritating dust!) as a tan solid. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=11.2, 5.6 Hz, 2H), 3.18 (s, 3H).