Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@@H:12]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])[CH2:11]OC(C)(C)[O:8][CH2:7]1)(=[O:4])=[O:3].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([C@@H:12]1[CH2:11][O:26][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])=[N:13]1)[CH2:7][OH:8])(=[O:3])=[O:4]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C2=N[C@H]([C@H](CO)OS(C)(=O)=O)CO2)c1C
Temperature: 25 °C

Procedure:
(5R, 6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide (compound [9], 34.2 g, 82.3 mmol) was dissolved in dichloromethane (340 ml) and boron trifluoride-diethyl ether complex (30.4 ml, 247 mmol) was added over 5 minutes with stirring at room temperature. The mixture was stirred for 40 hours at room temperature. Triethylamine (34.5 ml, 247 mmol) was added at not more than 15° C. and the solvent was distilled away under reduced pressure to ⅕ volume. The residue was diluted with ethyl acetate (340 ml) and washed successively with 10% brine (340 ml), 10% brine (340 ml) containing citric acid (17 g), and saturated brine (340 ml). After drying over magnesium sulfate, the solution was concentrated to 36 g to give a crude product of (2R)-2-methanesulfonyloxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)ethanol (compound [10]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:50])[C:27]([C:29]1[N:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([C:48]#[N:49])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:32]2[N:33]=[C:34](Cl)[N:35]=[CH:36][C:31]=2[CH:30]=1)=[O:28]>>[C:48]([C:45]([C:42]1[CH:41]=[CH:40][C:39]([N:38]2[C:32]3[N:33]=[C:34]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][CH:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:35]=[CH:36][C:31]=3[CH:30]=[C:29]2[C:27](=[O:28])[N:26]([CH3:25])[CH3:50])=[CH:44][CH:43]=1)([CH3:47])[CH3:46])#[N:49]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C#N)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccc(C(C)(C)C#N)cc1
Yield: 89 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-[4-(cyano-dimethyl-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave tert-butyl 3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (160 mg) in 89% yield. MS m/z 664.7
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4]Br.[CH3:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21]>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]3[C:10](=[O:21])[C:9]([CH3:8])([C:18]=2[CH:17]=1)[CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2]3
Reactant: CC(C)(CBr)CBr
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Product: COc1ccc2c(c1)C1(C)CC(C)(C)CC(C2)C1=O

Procedure:
By treating 1,3-dibromo-2,2-dimethyl propane and 1-methyl-7-methoxy-2-tetralone in the manner described in Example 1, one may prepare the title compound.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.C1C=CC=CC=1.Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][S:23]([C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=4)(=[O:25])=[O:24])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC12CCCc3cc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
6a-Methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.100 g) was dissolved in pyridine (5 ml) and anhydrous benzene (2 ml), the solution was added with 4-chlorosulfonylbenzoic acid (0.115 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight at room temperature. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.110 g, yield: 57%) as colorless needles (melting point: 215-217° C.).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20]>CN(C)C=O>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:12][C:7]1[C:6]2[C:11](=[C:2]([O:16][CH2:13][CH:2]([CH2:11][CH3:10])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CCCCC(CC)CBr
Reactant: Oc1cccc2c(O)cccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cccc2c(OCC(CC)CCCC)cccc12
Reaction time: 24 h
Yield: 133.3 %

Procedure:
5.0 g of 1,5-dihydroxynaphthalene (31.2 mmol) and 43.1 g of potassium carbonate (311 mmol) were dissolved in 50 mL of dimethylformamide (DMF). 18.0 g of 2-ethylhexyl bromide (93.2 mmol) was added thereto and stirred at 1000 for 24 hours. After the mixture was quenched with water, extracted with ethylacetate, and sequentially washed with water and salt water, excess water was removed using magnesium sulfate, followed by column chromatography, thereby obtaining 8.0 g of the title compound (66.6%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20][N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1nnn[nH]1
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cn2cnnn2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine tetrazole (0.45 g, 6.42 mmol) and dimethylformamide (6 mL). Cool in an ice bath and add sodium hydride (0.26 g, 60% i oil, 6.5 mmol). After 30 minutes, warm to ambient temperature. Add a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.13 g, 4.12 mmol) in dimethylformamide (10 (mL). Heat to 75° C. After 5.5 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 7/3 hexane/ethyl acetate to give methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate: Rf=0.67 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:26]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:27][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1cccc2ccccc12
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](CCO)=[C:18]([N+:29]([O-:31])=[O:30])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][C:18]=1[N+:29]([O-:31])=[O:30])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c2ccccc2c1CCO
Solvent: c1ccncc1
Product: CC(=O)OCCc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Reaction time: 8 h

Procedure:
Acetic anhydride (0.35 mL, 3.71 mmol) was added to a solution of 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethanol ((0.3 g, 0.93 mmol) in dry pyridine (3 mL) at room temperature and stirred overnight. The mixture was concentrated and dissolved in AcOEt (50 mL). The organic layer was washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and then the organic layer was dried (Na2SO4) and concentrate. The residue was purified by silica-gel column (AcOEt: Petroleum ether=1: 6) to yield 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethyl acetate ((0.21 g, 62%) as a yellow solid. mp 82-87° C.; 1H NMR (CDCl3, 500 MHz) δ 8.43 (d, 8.5, 1H), 8.33 (d, 8.5, 1H), 7.33 (dt, 1.0, 7.5, 1H), 7.66 (dt, 1.0, 7.0, 1H), 7.54 (d, 7.5, 2H), 7.45 (t, 7.5, 2H), 7.40 (t, 7.0, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 4.47 (t, 7.0, 2H), 3.55 (t, 7.0, 2H), 2.06 (s, 3H); EIMS m/z 388 (M+Na+); IR (neat) νmax 1738, 1593, 1527, 1514, 1466, 1424, 1365, 1337, 1235, 1104, 1043, 770, 752, 698 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH2:12][CH3:13].S(Cl)(Cl)=O.S(=O)=O.Cl>ClC1C=CC=CC=1>[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH2:12][CH3:13]
Reactant: CCCOc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)O
Agent: Cl
Agent: O=S=O
Solvent: Clc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCOc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid and 15.1 g (0.1 mol) of m-n-propoxy-aniline were dissolved in 100 ml of chlorobenzene. An 11.9 g (0.1 mol) amount of thionylchloride was added dropwise to the prepared solution at 40°-50°C, and the mixture was stirred at 90°-95°C for 4 hours, whereby sulfur dioxide and hydrogen chloride were continuously generated. After the reaction, the reaction mixture was poured into ice water and extracted with a mixture of benzene and hexane. The product was recrystallized from the mixed solvent to obtain 23.6 g (88%) of white needles having a melting point of 92°-94°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[C:20]1([NH:18][C:16]2[N:17]=[C:10]3[C:9]([C:6]4[CH:7]=[N:8][CH:3]=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][N:11]3[N:15]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccn3nc(N)nc23)cn1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: COc1ccc(-c2cccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)cn1
Product: c1ccc(Nc2nc3c(-c4cccnc4)cccn3n2)cc1

Procedure:
8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 2-methoxypyridine-5-boronic acid (1.0 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a tan solid (0.58 g, 51%). MP=157-158° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.91 (d, J=2.5 Hz, 1H), 8.54 (dd, J=6.6, 0.9 Hz, 1H), 8.44 (dd, J=8.7, 2.5 Hz, 1H), 7.73 (dd, J=7.6, 1.0 Hz, 1H), 6.97 (t, J=6.9 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.12 (s, 2H), 3.92 (s, 3H). MS=242 (MH)+. 8b) [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine and phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine were prepared from 8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4145 mmol) and 4-(4-bromo-phenyl)-morpholine (120.0 mg, 0.4956 mmol) in analogous manner to Example 2d. [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (0.037 g, 22%). MP=200-202° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.75 (d, J=2.3 Hz, 1H), 8.39 (d, J=6.3 Hz, 1H), 8.29 (dd, J=8.8, 2.6 Hz, 1H), 7.54-7.48 (m, 3H), 7.00-6.87 (m, 4H), 6.67 (s, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 4H), 3.13-3.09 (m, 4H). MS=403 (MH)+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[C:12]([OH:16])([CH3:15])(C)C.[N+:17]([C:20]1C=C[N+]([O-])=[CH:22][CH:21]=1)([O-])=O>O.C(OCC)(=O)C>[CH2:1]([O:6][C:22]1[CH:21]=[CH:20][NH:17][C:12](=[O:16])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCO
Reactant: CC(C)(C)O
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCOc1cc[nH]c(=O)c1
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of pentanol (2.7 g, 31 mmol) and tert-butoxide (3.5 g, 31 mmol) in solvent of tert-butanol was stirred for 1 hr at room temperature followed by addition of 4-nitropyridine-N-oxide (4 g, 28.6 mmol). After the reaction was done, the resulting solution was worked up with ethyl acetate and water, separated and the organic solvent was dried completely. After the addition of toluene, the solvent was removed under a reduced pressure. Acetic anhydride (40 ml) was added to the residual mixture and refluxed for 3 hrs. Acetic anhydride was dried completely followed by adding of MeOH (20 ml) and 3N NaOH (5 ml) and stirring 1 hr. MeOH was dried adequately then the residual mixture was made neutral with 6N HCl. The resulting solution was extracted with Ethyl acetate (80 ml) and subjected to silica gel column chromatography (ethyl acetate/MeOH, 10:1) to obtain the titled compound (2.3 g, 56%).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([O:48]CC)=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([OH:48])=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:25]1
Reactant: CCOC(=O)c1sc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)O
Yield: 86 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(2-(1H-indol-3-yl)ethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 86% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.09-6.95 (m, 2H), 3.98 (t, J=6.0 Hz, 2H), 3.61-3.50 (m, 4H), 2.94 (t, J=6.0 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]>O.C(O)C>[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[N:2][OH:3])=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=NO)cc1
Temperature: 95 °C
Yield: 89.9 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143.0 mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100 ml) at 30° C. was added a hot solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (5.72 g, 20.0 mmol) (obtained from preparation 3) in ethanol (100 ml). The reaction mixture was immersed in a preheated oil bath (95° C.) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and concentrated to a volume where crystals of oxime started separating out and the mixture was kept aside for 30 min. to 1 h at 25° C. The resultant crystals were filtered and washed with water and dried to obtain the title compound (5.42 g, 90%).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH2:5](N)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.O.C1(C=C(O)C=C(O)C=1)O.O>CS(C)=O>[N+:1]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][C:21](OC)=[O:22].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:22][CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)CC1=C(C)c2ccccc2/C1=C\c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 3 (270 mg, 0.83 mmol) in dry THF (5 mL) at 0° C. was added a solution of diisobutyl aluminum hydride (1M) in toluene (2.1 mL, 2.1 mmol, 3.5 eq). After 1 hour, the reaction mixture was added dropwise to a solution of 1N aqueous HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate-hexane to afford pure title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9](CC1CCCCC1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:26](Cl)[CH2:27]Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:26][CH2:22][CH2:21][CH2:20][CH2:24]1)[C:10]([O:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCCC1
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)OC1CCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 235.5 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (5 g, 19.4 mmol) in DMF (50 mL) at 0° C. was added cyclopentanol (8.8 ml, 97.15 mmol), EDC (4.09 g, 21.37 mmol) and finally DMAP (237 mg, 1.94 mmol). The reaction mixture was warmed to RT and stirred for 18 h. The DMF was removed in vacuo to give a clear oil. This was separated between water and EtOAc. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (25% EtOAC in heptane) to yield the desired product as a clear oil (14.87 g, 55%). 1H NMR (300 MHz, d6-DMSO) δ: 7.09 (1H, d), 5.08 (1H, t), 3.76 (1H, t), 1.50-1.85 (10H, br m), 1.39 (9H, s), 1.00-1.25 (9H, br m).
Reaction SMILES: F[C:2](F)([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:4](I)[CH:5]([OH:7])[CH3:6].[OH2:14].Cl.[NH2:16]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:10][C:9]([F:12])([F:11])[C:2]1[O:14][N:16]=[C:4]([CH:5]([OH:7])[CH3:6])[CH:3]=1
Reactant: O
Reactant: NO
Reactant: CC(O)C(I)=CC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(O)c1cc(C(F)(F)F)on1

Procedure:
7.49 g of 5,5,6,6,6-pentafluoro-3-iodo-3-hexene-2-ol was dissolved in 70 ml of ethanol, and 30 ml of water, 3.34 g of hydroxylamine hydrochloride and 17.94 g of potassium carbonate were then added. The mixture was stirred and heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.53 g of 1-(5-trifluoromethyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](=[O:22])([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:11]([O:1][C:2]1[CH:9]=[C:8]([O:22][CH2:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 60 %

Procedure:
2,4-Dihydroxybenzaldehyde [IV] (14.5 g) was dissolved in ethanol (60 ml) and then thereto were added benzyl chloride (30 ml) and sodium carbonate (1.7 g), followed by reflux under heating for 5 hours. Insoluble matters were removed by filtration. The filtrate was allowed to stand for cooling and then the produced solid was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzaldehyde [V] (20 g, yield 60%). Melting point: 89°-90° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1.C(N(CC)CC)C>CO>[CH3:2][N:3]([CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: CNC
Reactant: BrCCOc1cc(-c2ccccc2)on1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)CCOc1cc(-c2ccccc2)on1
Yield: 62.9 %

Procedure:
After dimethylamine hydrochloride (815 mg) was dissolved in methanol (50 ml), 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and triethylamine (2.8 ml) were added thereto, followed by reflux of the resulting mixture for 8 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ether (20 ml), and the solution was washed with a diluted aqueous NaCl solution (20 ml), followed by drying of the organic layer over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (146 mg, 63%) as colorless crystals.