Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1.[CH3:23][NH:24][CH3:25].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1
Reactant: CNC
Reactant: Cn1c(C=Cc2ccccc2OCCCl)nc2ccccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)CCOc1ccccc1C=Cc1nc2ccccc2n1C

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-1-methyl-benzimidazole was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-1-methyl-benzimidazole and dimethylamine, and the free base was converted into its dihydrochloride, yielding 18% of theory of the compound of the formula ##STR12## which had a melting point of 208° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O=[C:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])=[CH:6]1.[OH-].[K+]>O.Cl.C(N)C>[CH2:1]([N:3]=[C:5]1[CH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])=[CH:6]1)[CH3:2]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CCN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCN=C1C=C(C)CC(C)(C)C1
Temperature: 10 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
Ethylamine (42 ml of a 70% solution in water, 530 mmol) is added slowly to a stirred mixture of isophorone (9.67 g, 70 mmol) and ethylamine hydrochloride (0.29 g, 3.5 mmol) at -7° C. After the addition is complete, the temperature of the mixture is allowed to rise to room temperature, and the mixture is stirred for a further 72 hours. The mixture is subsequently cooled to 10° C., and potassium hydroxide (44.9 g, 800 mmol) is added in portions. After 45 minutes, ice is added and the mixture is stirred. The organic phase is then separated, dried over sodium sulfate and evaporated in vacuo to give the crude product (11.0 g, 95%) as a yellow oil, which is used immediately without further purification in the following step.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([NH2:18])[CH3:17].C[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>ClCCl>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:16]([CH3:17])[N:18]([C:25]([C:24]4[CH:28]=[CH:29][C:21]([OH:20])=[CH:22][CH:23]=4)=[O:26])[C:4]=2[CH:5]=1)=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3
Reactant: CC(N)c1cc(F)ccc1-c1ccc(F)cc1F
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
4-Methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzamide—A stirred solution of 1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethylamine (0.71 g, 2.84 mmol) in dichloromethane (5 mL) was treated with 4-methoxybenzoyl chloride (0.51 g, 3.0 mmol), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol). The reaction was stirred at room temperature for twelve hours, and the solvent evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl tert-butyl ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.98 g, 2.54 mmol, 90%) as a homogeneous, colorless, crystalline solid, m.p. 163-165° C.; MS [(+ESI), m/z]: 386 [M+H]+; IR (Solid), vmax: 3257, 1620, 1606, 1503, 1329, 1249, 1175, 1032, 844, 777, 670 cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (d, J=5.4 Hz, 3H), 3.80 (s, 3H), 4.93 (broad s, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.14 (td, J=8.5, 2.7 Hz, 1H), 7.22 (dd, J=8.5, 5.9 Hz, 2H), 7.37 (t, 2H), 7.46 (d, J=9.1 Hz, 1H), 7.61 (d, J=4.7 Hz, 1H), 7.83 (d, J=7.2 Hz, 2H), 8.66 (d, J=3.9 Hz, 1H), exists as approximate 2:1 mixture of rotamers; Anal. calcd for C22H18F3NO2: C, 68.57; H, 4.71; N, 3.63. Found: C, 68.65; H, 4.80 N, 3.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])/[CH:14]=[CH:15]/[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:17])/[CH:14]=[CH:15]/[CH3:16])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2ccccc2c1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccc2cc(OC)ccc2c1
Yield: 69 %

Procedure:
2-methoxynaphthalene (158 mg), crotonoyl chloride (124 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (156 mg).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:9]1([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][N:17]=[C:18]=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:9]1([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][NH:17][C:18]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])=[O:19])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=C=NCC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(NCC(c1ccccc1)c1ccccc1)n1ccc(=O)[nH]c1=O
Yield: 76 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from uracil (0.37 g, 3.34 mmol); 1.3 equivalents of 2,2-diphenylethyl isocyanate were used herein. The crude was taken up in dichloromethane; the title compound precipitated and was filtered off. The title compound (0.85 g, 76%) was isolated as white powder. 1H NMR (400 MHz, DMSO-d6): δ 3.97 (dd, J=8, 0, 5.5 Hz, 2H), 4.32 (t, J=7.9 Hz, 1H), 5.78 (d, J=8.4 Hz, 1H), 7.17-7.25 (m, 2H), 7.27-7.39 (m, 8H), 8.19 (d, J=8.4 Hz, 1H), 9.20 (t, J=5.5 Hz, 1H), 11.66 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 44.93, 50.61, 103.98, 127.09, 127.18, 128.60, 138.79, 142.58, 142.91 150.27, 151.93, 161.03. MS (ESI) m/z: 334 [M-H]−.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([OH:22])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>O1CCOCC1>[C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([Cl:25])=[O:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Solvent: C1COCCO1
Product: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2

Procedure:
1,4-Dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2 g) is reacted with thionyl chloride (1 ml) in dioxane (40 ml) at reflux temperature for 2 hours. After cooling the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (15 ml) and reacted for 2 h under stirring at room temperature with the carbanion obtained by treatment of cyanacetic acid, 2-morpholinomethylbenzylamide (1.95 g) with 50% sodium hydride (0.39 g) in anhydrous dioxane/dimethylformamide 9:1 (20 ml) at room temperature.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:16][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1.CCN(CC)CC.[Cl:43][C:44]1[C:45]([OH:55])=[C:46]([S:51](Cl)(=[O:53])=[O:52])[CH:47]=[C:48]([Cl:50])[CH:49]=1>C(Cl)Cl>[Cl:43][C:44]1[C:45]([OH:55])=[C:46]([S:51]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[CH:6]=[C:5]([CH2:16][N:17]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:4]=2)(=[O:53])=[O:52])[CH:47]=[C:48]([Cl:50])[CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CN)cc(-c3ccc(F)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CNS(=O)(=O)c3cc(Cl)cc(Cl)c3O)cc(-c3ccc(F)cc3)c2)cc1
Yield: 51.6 %

Procedure:
To a solution of N-((5-(aminomethyl)-4′-fluorobiphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (40 mg, 0.081 mmol) and Et3N (40 mg, 0.395 mmol) in CH2Cl2 (4 mL) at rt was added solid 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (21.24 mg, 0.081 mmol) with stirring. The reaction was complete within an hour. The mixture was concentrated and the residue was purified by prep HPLC to provide the desired product as a white solid (30 mg). 1H NMR (CDCl3): δ 7.72 (d, J=8.2 Hz, 2H), 7.51 (d, J=2.2 Hz, 1H), 7.34-6.83 (m, 14H), 5.32 (t, J=6.0 Hz, 1H), 4.25 (s, 2H), 4.245 (s, 2H), 4.12 (d, J=6.0 Hz, 2H), 2.43 (s, 3H); MS (ESI): (M+H)+=717.
Reaction SMILES: C1(C[N:5]([C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[CH2:6][C:7]2[C:8]([O:13]C)=[N:9][CH:10]=[CH:11][CH:12]=2)CC1.Cl.C(O[CH2:41][CH3:42])(=O)C.C(=O)([O-])O.[Na+].[C:48](OCC)(=O)[CH3:49]>C(O)C>[CH:41]1([CH2:42][CH:6]([NH:5][C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[C:7]2[C:8]([OH:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:49][CH2:48]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(Cc3cccnc3OC)CC3CC3)c(SC)nn12
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(CC3CC3)c3cccnc3O)c(SC)nn12

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine (63 mg) in ethanol (1 mL), a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added at room temperature and the mixture was heated to reflux for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture for neutralization while cooling on ice, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (49 mg) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1cccnn1
Product: CNC(=O)NCCSCc1cccnn1

Procedure:
By the same procedure of Example 24, 3-[(2-aminoethyl)thiomethyl]pyridazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[NH2:8][C@@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C/[C@H](C)N
Yield: 98 %

Procedure:
A solution of methyl (2E)(4S)-4-[(tert-butoxy)carbonylamino]pent-2-enoate (3.083 g, 13.45 mmol) in 4N hydrogen chloride in dioxane was stirred at room temperature for 1 hour. The volatiles were evaporated to give the title compound (2.2 g, 98%): ES-MS (m/z) 130.3 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH2:24][C:25]3[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a solution of methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylbenzoate (119 mg) in EtOAc (8 m1) and MeOH (10 ml) was added 10% Pd/C (wet) (60 mg) and the mixture was stirred under hydrogen atmosphere at 3 atm at room temperature for 18 hours. The catalyst was removed by filtration and the filtrate was evaporated to give methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}-2-methyl-benzoate (115.3 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:16](Br)[CH3:17]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5](=[O:6])[CH3:7])[CH2:17][CH2:16]1)=[O:8]
Reactant: CC(Br)Br
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(C)=O)CC1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
56 g of acetoacetic acid methyl ester 3 is dissolved in 500 ml of acetone, and 276.2 g of potassium carbonate as well as 86 ml of dibromoethane are added while being cooled with ice. It is heated under nitrogen to 50° C. and stirred for 72 hours at this temperature. After cooling, the mixture is diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is distilled in a vacuum, whereby 66 g of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.I[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][C@@:2]2([CH3:1])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:7]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ICC1CCCC1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Product: C[C@@]1(CC2CCCC2)N[C@@H](c2ccccc2)COC1=O

Procedure:
The compound was prepared according to the procedure outlined in Preparation 1 using (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (iodomethyl)cyclopentane. The total amount of compound synthesised was 0.426 g.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:4]([Cl:32])[CH:3]=1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[C:4]([Cl:32])[CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 623.3 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Li+].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 2-pyridylacetate (6.81 mL, 50 mmol) was added dropwise to LHMDS (1.0M in THF, 50 mL) and THF (65 mL) cooled to 0° C. After 30 minutes iodomethane (3.97 g, 63.5 mmol) was added to the solution. After stirring for 1 hour at 0° C. the solution was concentrated and the residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CHCl3-d): δ 8.56 (d, J=4.9 Hz, 1H); 7.66 (td, J=7.6, 1.8 Hz, 1H); 7.18 (dd, J=7.6, 4.9 Hz, 1H); 3.96 (q, J=7.2 Hz, 1H); 3.69 (s, 3H). 1.56 (d, J=7.2 Hz, 3H). m/z 166.5 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=3[C:21]([OH:23])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:14]4[C:13]=3[C:21](=[O:23])[N:25]([CH:26]3[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]3=[O:28])[C:15]4=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Yield: 29 %

Procedure:
A mixture of 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid (1.2 g, 3.8 mmol), alpha-amino-glutarimide hydrochloride (0.66 g, 4.0 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(benzo[1,3]dioxol-5-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.45 g, 29% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 μm, 50/50 CH3CN/0.1% H3PO4, 4.06 min (98.6%); mp, 229-231° C.; 1H NMR (DMSO-d6) δ 2.02-2.05 (m, 1H, CHH), 2.55-2.62 (m, 2H, CH2), 2.82-2.94 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.26 (s, 2H, CH2), 6.03 (s, 2H, CH2), 6.93-7.85 (m, 6H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.91, 48.74, 70.00, 101.05, 108.10, 108.18, 115.49, 116.61, 120.28, 121.25, 129.78, 133.24, 136.95, 147.04, 147.38, 155.44, 165.30, 166.76, 169.89, 172.74. Anal Calcd For C21H16N2O7: C, 61.77; H, 3.95; N, 6.86. Found: C, 61.44; H, 3.72; N, 6.79.
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O>O>[OH:13][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cnc(N)c(OC)n1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cnc(O)c(OC)n1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-amino-3,5-dimethoxypyrazine (0.02 mole) in 300 ml. of 6 M sulfuric acid at 0°-5° C. is treated with 0.022 mole sodium nitrite in 25 ml. of water at such a rate to insure that the temperature of the reaction mixture does not rise above 5° C. After standing 45 minutes at 0°-5° C., a little urea is added to destroy excess nitrous acid and the mixture then is treated with sodium hydroxide solution until strongly basic. The reaction mixture is warmed to 60° C. for one hour and then brought to pH 8.5. The mixture is concentrated to a third of the original volume and cooled in the refrigerator overnight. The product is separated by filtration and dried in vacuo, recrystallized from a suitable solvent to give 2-hydroxy-3,5-dimethoxypyrazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 99.9 %

Procedure:
To a solution of 3-hydroxyquinoline (1.00 g) and 3-chloro-4-fluoronitrobenzene (1.21 g) in Acetone (20 ml), was added K2CO3 (2.86 g). The mixture was refluxed for 1 hr. After cooling the reaction mixture was filtered through a short celite pad. The filtrate was concentrated to provide compound 198 (2.07 g, quant.) as a brown oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]([CH2:16][C:17]([O:19]C)=[O:18])[C:14](=[O:21])[C:13]3([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]3)[N:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1>CO>[C:31]([O:30][C:28]([N:12]1[C:13]2([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]2)[C:14](=[O:21])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH2:11]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccc(F)cc2)N(CC(=O)O)C(=O)C12COCCOC2

Procedure:
2.0 ml (2.0 mmol) of a 1N aqueous sodium hydroxide solution were added to 0.29 mg (0.61 mmol) tert-butyl 3-(4-fluorophenyl)-4-(2-methoxy-2-oxoethyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml MeOH. After 1 h at RT MeOH was distilled off and the aqueous solution was acidified with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.CC(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:12]([CH3:17])[CH3:13])[CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.6 %

Procedure:
5-Fluoro-2-nitrophenol (48 g) was dissolved in dry tetrahydrofuran (THF) (300 mL). Triphenylphosphine (88 g) and 2-propanol (47 mL) were added, and the resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (66 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred over night. The solvent was evaporated in vacuo and the resulting mixture was filtered through silica (heptane/ethyl acetate 1:1). The solvent was evaporated in vacuo and the resulting mixture was recrystallised from heptane/ethyl acetate (1:1). The organic phase was separated from the crystalline solid by filtration, the solvent was evaporated in vacuo, and the remaining product was purified by flash chromatography (silica gel, heptane/ethyl acetate 9:1), yielding the title compound as colourless oil (47.2 g, 78%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[CH:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-isopropylphenylboronic acid as starting materials in step D. MS (ES): 502.2 [M+H]+.