Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)O)cc1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 52 (900 mg, 3.25 mmol) in THF/water, 3:1 (10 mL) was added lithium hydroxide monohydrate (273 mg, 6.5 mmol), and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed in vacuo. The aqueous layer was extracted with diethyl ether (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined DCM fractions were dried and evaporated to yield the title compound (750 mg, 2.85 mmol, 88%) as a white solid. [α]D23 −23.2 (c. 0.1, EtOH). Mp 75° C. 1HNMR (D6 acetone, 300 MHz): δ 7.27 (d, J=7.8 Hz, 1H, NH); 7.17 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.86 (d, J=8.7 Hz, 21H, ArH3′ and ArH5′); 6.06 (m, 1H, H2″); 5.40 (dd J=1.5 Hz, 17.5 Hz, 1H, H3a″); 5.23 (dd, J=1.5, 10.5 Hz, 1H, H3b″); 4.67 (dd, J=5.1, 8.1, 10.5 Hz 1H, H2); 4.53 (d, J=5.1 Hz, 2H, H1″); 3.11 (dd, J=5.4, 14.1 Hz, 1H; 3Ha); 2.93 (dd, J=8.1, 14.1, 1H, 3Hb); 1.89 (s, 31H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH+]. HRMS calcd for C14H18NO4 264.123583, found 264.123770.
Reaction SMILES: ClC1C=CC(OC=C(C)C)=CC=1.[N+](=CC(OCC)=O)=[N-].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([O:26][CH:27]2[CH:29]([C:30]([O:32]CC)=[O:31])[C:28]2([CH3:36])[CH3:35])=[CH:24][CH:23]=1>[Cu]>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH:27]2[CH:29]([C:30]([OH:32])=[O:31])[C:28]2([CH3:35])[CH3:36])=[CH:37][CH:38]=1
Reactant: CCOC(=O)C1C(Oc2ccc(Cl)cc2)C1(C)C
Agent: [Cu]
Agent: CC(C)=COc1ccc(Cl)cc1
Agent: CCOC(=O)C=[N+]=[N-]
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O

Procedure:
Following the procedure of Example 1B, 7.2 g (0.040 mol) of 3-(4-chlorophenoxy)-2-methyl-2-propene and 0.2 g copper powder are reacted with 8.7 g (0.079 mol) ethyl diazoacetate to yeild ethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate, which is then hydrolyzed to give 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][C@@H:5]([NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1)[NH:25][C:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:23]2)=O)[CH2:6][S:7]CC1C=CC(OC)=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][C@@H:5]1[CH2:6][S:7][C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=2)[NH:25][C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:23]3)=[N:17]1
Reactant: COC(=O)C[C@H](CSCc1ccc(OC)cc1)NC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H]1CSC(c2cc([N+](=O)[O-])c3[nH]c(-c4ccccc4)cc3c2)=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
(R)-4-(4-methoxy-benzylsulfanyl)-3-[(7-nitro-2-phenyl-1H-indole-5-carbonyl)-amino]-butyric acid methyl ester (533 mg, 1 mmol) prepared in Step A was dissolved in DCM (10 mL). Phosphorus pentachloride (406 mg, 2 mmol) was added thereto, and the mixture was stirred for 5 h at room temperature. The reaction was quenched by saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography to give the title compound (240 mg, Yield 60%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])=[O:3].[C:18]1([CH2:24][CH2:25][CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:2]([C:4]1[C:9]([O:10][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])(=[O:3])[CH3:1]
Reactant: BrCCCc1ccccc1
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Product: COc1c(C(C)=O)c(OCCCc2ccccc2)c(OC)c2occc12
Yield: 85.8 %

Procedure:
Khellinone (59 mg, 0.25 mmol) and 3-(phenyl)propylbromide (46 μL, 0.30 mmol) were treated as described under General Procedure A to afford the title compound (76 mg, 85%) as a colourless solid: 1H NMR (300 MHz, CDCl3): δ 2.03 (m, 2H), 2.53 (s, 3H), 2.76 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 4.03 (s, 3H), 4.08 (t, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 7.14-7.30 (m, 5H), 7.56 (d, J=2.4 Hz, 1H). MS (ES+) m/z 355.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)[CH:17]=[C:18]([F:29])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1
Yield: 71 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (1.6 equiv.) at 100° C. for 30 min in microwave to give methyl 6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinate in 71% yield. LC/MS=338.0 (MH+), Rt=0.85 min.
Reaction SMILES: CNCC(O)=O.C([O:9][C:10](=[O:43])[C:11]([NH:35]C(OC(C)(C)C)=O)([CH2:25][CH2:26][N:27]([CH2:29][C:30]([O:32]CC)=[O:31])[CH3:28])[CH2:12][CH2:13][CH2:14][CH2:15][B:16]1[O:20]C(C)(C)C(C)(C)[O:17]1)C.[ClH:44]>O>[ClH:44].[ClH:44].[NH2:35][C:11]([CH2:25][CH2:26][N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28])([CH2:12][CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17])[C:10]([OH:43])=[O:9]
Reactant: CCOC(=O)CN(C)CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CNCC(=O)O
Agent: Cl
Solvent: O
Product: CN(CCC(N)(CCCCB(O)O)C(=O)O)CC(=O)O
Temperature: 25 °C
Yield: 76 %

Procedure:
2-Amino-6-borono-2-(2-((carboxymethyl)(methyl)amino)ethyl)hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except 2-(methylamino)acetic acid is used as the amine in step 6. The final step is as follows: a solution of (R/S)-2-tert-butoxycarbonylamino-2-[2-(2-ethoxycarbonylmethyl-methyl-amino)-ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (138 mg) in 6 N hydrochloric acid (6 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a colorless foam (72 mg, 76%); 1H NMR (D2O, 300 MHz) δ 3.94 (s, 2H), 3.37 (m, 1H), 3.20 (m, 1H), 2.83 (s, 3H), 2.24 (t, J=8 Hz, 2H), 1.66-1.88 (m, 2H), 1.27 (m, 3H), 1.11 (m, 1H) and 0.63 (t, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH:24](O)([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][N:10]([CH:24]([CH3:26])[CH3:25])[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)N(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 150.5 %

Procedure:
The compound (2.22 g, 6.43 mmol) obtained in step A, isopropanol (0.65 ml, 8.46 mmol), and triphenylphosphine (1.85 g, 7.05 mmol) were dissolved in tetrahydrofuran (50 ml) and the mixture was stirred under ice-cooling. Thereto was slowly added 40% diisopropyl azodicarboxylate-toluene solution (5 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and diluted with diethyl ether, and the precipitated colorless solid was filtered off. The mother liquor was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give tert-butyl[2-{isopropyl[(2-nitrophenyl)sulfonyl]amino}ethyl]carbamate (3.75 g) as a colorless crude oil. This was dissolved in dichloromethane (10 ml), 4N hydrochloric acid-dioxane solution 10 ml) was added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with diethyl ether, and the mixture was extracted with water. The aqueous layer was alkalified with aqueous sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.39 g, yield 75%) as a yellow oil.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[CH:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9]=[O:10]>>[CH2:4]([C:5]([CH2:1][OH:3])([CH2:9][OH:10])[CH2:6][CH3:7])[OH:8].[CH:1]([O-:3])=[O:2]
Reactant: C=O
Reactant: CCCC=O
Agent: O=C[O-]
Product: CCC(CO)(CO)CO

Procedure:
In the process of the invention, n-butyraldehyde is firstly reacted with formaldehyde in the presence of a base. This reaction can be carried out in one or more stages. In the single-stage variant, the starting materials are reacted directly to form trimethylolpropane and a formate salt. In a two-stage variant, n-butyraldehyde and formaldehyde are firstly reacted in the presence of catalytic amounts of base to form 2,2-dimethylolbutanal, purification or separation steps are carried out if desired and only then is the 2,2-dimethylolbutanal reacted with further formaldehyde in the presence of stoichiometric amounts of base to form trimethylolpropane and formate salt.
Reaction SMILES: [NH:1]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][CH:3]1[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:1][C:2]1=[O:13]
Reactant: O=C1CCCCc2ccccc2N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCCC1Br

Procedure:
To a solution of 4.7 g of 3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one, J. Chem. Soc. (C), 2176 (1969) in chloroform (75 ml), phosphorus pentachloride (5.9 g) is added in portions, while maintaining the temperature at 0°-5° C. When addition is complete, iodine (60 mg) is added, followed by bromine (4.5 g), which is added dropwise over five minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue partitioned between ice/water (60 ml) and dichloromethane (100 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether/hexane mixtures. Concentration of the appropriate fractions yields 3-bromo-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)-hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. was treated sequentially with 50% sodium hydroxide (1.3 g) and benzoyl chloride (0.728 g). The mixture was stirred overnight. The solids were removed by filtration and washed with water to afford N'-t-butyl-N-(2-pyridinecarbonyl)-N'-benzoylhydrazine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:26])[N:19]2[CH:27]=[N:28][C:29]([C:30]3[O:34][N:33]=[C:32]([CH:35]4[CH2:37][CH2:36]4)[N:31]=3)=[C:18]2[N:17]=1>CN(C=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][OH:1])=[N:17][C:18]1[N:19]2[CH:27]=[N:28][C:29]=1[C:30]1[O:34][N:33]=[C:32]([CH:35]2[CH2:37][CH2:36]2)[N:31]=1
Reactant: OC[C@H]1CCCN1
Reactant: Clc1cccc2c1c(Cl)nc1c(-c3nc(C4CC4)no3)ncn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC[C@H]1CCCN1c1nc2c(-c3nc(C4CC4)no3)ncn2c2cccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-2-hydroxymethylpyrrolidine (70 mg) and triethylamine (90 mg) dissolved in dry DMF (1 ml) was added dropwise to a stirred suspension of 5,6-dichloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinazoline (0.20 g) in dry DMF (5 ml) at 0° C. After 20 min. the reaction mixture was filtered. The filtrate was diluted with 15 ml of water and stirred at 0° C. for 10 min. The crystals which had formed were filtered off, rinsed with water, and dried to give the title compound as yellow crystals, m.p. 220°-221° C. Yield 0.15 g.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OOC(=O)c1ccccc1

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type D with two reactors of type B connected downstream in series. 1.72 kg/l·h of a 19.5% by weight solution of tert-butyl hydroperoxide and 9.5% by weight of sodium hydroxide in water and 0.49 kg/l·h of benzoyl chloride are fed to the first reactor. The metering rates are based on the total volume of the reactor arrangement in litres. Cooling with cooling water keeps the internal temperature in all reactors at 25° C. The organic phase is removed from the reaction mixture withdrawn from the third reactor, washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with demineralized water, and then dried with calcium chloride. 0.61 kg/l·h of tert-butyl peroxybenzoate is obtained (89.9% based on benzoyl chloride).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH3:30]>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: CCCBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(OC)ccc(-c2cccc3c2CCC3=O)c1OC
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (116 mg, 0.843 mmol) and propyl bromide (103 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 33.3%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]3)=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH:27]([C:30]1[N:34]=[C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:32][N:31]=1)([CH3:29])[CH3:28].ClCCl>>[CH3:24][C:21]1([CH3:25])[O:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:6]3[N:5]=[CH:4][N:3]=[C:2]([N:38]4[CH2:37][CH2:36][CH:35]([C:33]5[O:32][N:31]=[C:30]([CH:27]([CH3:29])[CH3:28])[N:34]=5)[CH2:40][CH2:39]4)[C:7]=3[N+:8]([O-:10])=[O:9])=[CH:13][CH:14]=2)[CH2:19][O:20]1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: CC1(C)OCC(c2ccc(Oc3ncnc(Cl)c3[N+](=O)[O-])cc2)CO1
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1noc(C2CCN(c3ncnc(Oc4ccc(C5COC(C)(C)OC5)cc4)c3[N+](=O)[O-])CC2)n1
Temperature: 27 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To an ice-cold solution of 4-chloro-6-(4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)-5-nitropyrimidine (500 mg, 0.0013 moles) and 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride (293 mg, 0.0015 mole) in dichloromethane (10 ml) diisopropyl ethyl amine (0.24 ml, 0.0016 mole) was added and the reaction mixture was stirred for 4 hours at 27° C. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic extract was successively washed with water & brine, dried over calcium chloride and evaporated under reduced pressure. The crude product so obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to yield 450 mg product as pale yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]3[N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:18]=[C:17]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:16]3)[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N:6]3[CH2:7][CH2:8][CH:3]([NH:2][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:4][CH2:5]3)[CH:10]=2)[CH2:16][C:17]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:18]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
5-[3-(4-Amino-piperidin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (50.0 mg, 0.11 mmol) prepared in Example 99, triethylamine (55.0 mg, 0.54 mmol) and methanesulfonyl chloride (18.5 mg, 0.16 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and 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 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[N:5]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:7][C:8]=1C(OCC)=O>C(O)(=O)C.Cl.C(O)C.S(=O)(=O)(O)O>[S:14]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]1=2)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 552.1 %

Procedure:
To a suspension of ethyl 5-hydroxy-1-tosyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (30 g, 8.04 mmol) in glacial acetic acid (180 mL), conc. hydrochloric acid (30 mL), ethanol (60 mL) water (30 mL) and conc. sulphuric acid (15 mL) were added at 10-15° C. The reaction mixture was warmed to room temperature and then heated to reflux for 15-16 h. The reaction mixture was cooled to room temperature and poured on to ice. A precipitate formed which was filtered and washed with water (200 mL×3) and dried under reduced pressure to afford 1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (14 g, 56%). 1H NMR: (400 MHz, CDCl3) δ: 7.71-7.69 (1H, d, J=9.6 Hz), 7.60 (2H, d, J=8.4 Hz), 7.54 (1H, t, J=8.4 Hz), 7.48 (1H, d, J=7.2 Hz), 7.40 (1H, t, J=7.2 Hz), 7.28 (2H, d, J=8.4 Hz), 3.87 (2H, t, J=6.4 Hz), 2.42 (3H, s), 2.42 (2H, m), 1.98 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[NH:4][C:5]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:6]=1[C:7]([O:9]C(C)(C)C)=[O:8]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[NH:4][C:5]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(2,6-dichloroanilino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 75-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(2,6-dichloroanilino)-4-phenethylbenzoic acid 9.4 mg of white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=[O:14]
Reactant: OCCCc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCCc1ccc2ccccc2c1
Yield: 53 %

Procedure:
Then, following a procedure similar to that described in the second part of Preparation 4, the whole of this 3-(2-naphthyl)propanol was reacted with 2.06 g of dimethyl sulfoxide, 3.35 g of oxalyl chloride and 7.34 ml of triethylamine in 45 ml of methylene chloride. The reaction mixture was worked up and purified as described in the second part of Preparation 4, to give 1.74 g (yield 53%) of 3-(2-naphthyl)propanal as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[C:19]([NH2:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:9][C:10]2[CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]3=[CH:18][C:19]=2[N:20]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: O=C(CBr)C(=O)CBr
Product: BrCc1nc2cc3ccccc3cc2nc1CBr

Procedure:
Following the procedure of Example 1, 1,4-dibromo-2,3-butanedione is condensed with 2,3-diaminonaphthalene to obtain 2,3-bis(bromomethyl)benzo[g]quinoxaline, m.p. 190°-191° C.; 1H NMR (DMSO-d6, 400 MHz): δ5.07 (s, 4H, CH2), 7.68 and 8.26 (double doublets, 4H, H-7 and H-8, H-6 and H-9, resp.), 8.78 (s, 2H, H-5 and H-10).