Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7]2.B(Br)(Br)Br.N>ClCCl>[ClH:1].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc2c(N3CCN(CCNC(=O)c4ccc(F)cc4)CC3)cccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: O=C(NCCN1CCN(c2cccc3cc(O)ccc23)CC1)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 0.85 g of the compound of Example 1, in base form, in 40 ml of dichloromethane is cooled to -20° C. under a nitrogen atmosphere. 10 ml of a molar solution of boron tribromide in dichloromethane are then added dropwise while the temperature is maintained at -20° C. When the addition is complete, the medium is slowly heated to room temperature and stirred at this temperature for one hour before being hydrolyzed with 2 ml of ammonia solution. The organic phase, separated after settling has taken place, is dried over anhydrous magnesium sulfate and the solvent evaporated off under vacuum; the residue is dissolved in 20 ml of ethanol and the hydrochloride is precipitated by adding 0.4 ml of 6N ethanolic hydrogen chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].[BH4-].[Na+]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2c1CCNC2

Procedure:
In close analogy to the procedure described above, 5-Nitro-isoquinoline is reacted with sodium borohydride to provide the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]2[CH2:7][C:8]3[N:13]4[CH:14]=[C:15](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[N:16]=[C:12]4[C:11](=[O:24])[NH:10][C:9]=3[C:25]=2[CH:26]=[CH:27][CH:28]=1)([OH:3])=[O:2].Cl>C(O)(=O)C>[C:1]([CH2:4][C:5]1[C:6]2[CH2:7][C:8]3[N:13]4[CH:14]=[C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[N:16]=[C:12]4[C:11](=[O:24])[NH:10][C:9]=3[C:25]=2[CH:26]=[CH:27][CH:28]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)/C=C/c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)O)c1C3
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)O)c1C3
Yield: 70 %

Procedure:
A mixture of 1.45 g of ethyl (E)-3-(9-carboxymethyl-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl)acrylate, 19 ml of concentrated hydrochloric acid and 78 ml of acetic acid is heated at reflux for 48 hours. The reaction mixture is filtered and the solid is washed with 2×20 ml of distilled water and then with 2×10 ml of acetone and finally dried under vacuum (1 mm Hg; 0.13 kPa) at about 60° C. 0.94 g of (E)-3-(9-carboxymethyl-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl)acrylic acid is obtained in the form of a beige solid melting above 260° C. [Analysis: C18H13N3O5, 0.89 HCl, 0.91 H2O, % calculated C: 61.54, H: 3.73, N: 11.96, O: 22.77, % found C: 61.8, H: 3.4, N: 11.9].
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[OH:21][CH2:22][CH2:23]N>>[O:21]1[CH2:22][CH2:23][N:2]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)=[CH:19][CH:20]=1
Reactant: NCCO
Reactant: Cc1cc(CCCCCOc2ccc(C#N)cc2)on1
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2)on1
Yield: 68 %

Procedure:
5-{5-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole [IX; R=CH3, R1, R2, R3, R4, R5 and R6 =H, Y=(CH2)5, oxazole at 4-position] was prepared by conversion of 5-[5-(4-cyanophenoxy)pentyl]-3-methylisoxazole to the corresponding ethyl imino-ester hydrochloride (m.p. 120°-121° C.) and reaction of the latter with 2-hydroxyethylamine in accordance with the procedure of Example 1, part (c). The product was obtained in 68% yield as a colorless solid, m.p. 87°-88° C.; monomethanesulfonate salt, m.p. 124°-125° C. The free base was obtained as a colorless solid, m.p. 102°-103.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:21][O:22][CH3:23])[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Clc1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c(-c2ccncc2)cnc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-(4-pyridyl) imidazole from Step A (200 mg, 0.78 mmol) in THF (8 mL) at room temperature was added sodium hydride (63 mg of a 60% oil dispersion, 1.57 mmol). After cooling to 0° C., methoxymethyl chloride (74 μL, 0.97 mmol) was slowly added. The reaction was stirred at 0 oC for 1 h, then at room temperature for 1 h. The reaction was quenched by the addition of 5% sodium bicarbonate solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with 5% sodium bicarbonate solution, water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-3% methanol in methylene chloride to yield the title compound as a pale yellow solid (172 mg, 72% yield), mass spectrum (CI) m/e=300 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[B].O1CCCC1>[Cl-].[NH4+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CCN(CC)C(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [B]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-N,N-diethyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (180 mg, 0.431 mmol) was added boron-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 2.2 mL, 2.2 mmol), and the mixture was stirred at 80° C. for 3 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (72.2 mg, 0.179 mmol, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([C:42](=[O:44])[CH3:43])=[CH:41][C:28]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([C:42](=[O:44])[CH3:43])=[CH:41][C:28]3=4)[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)C(=CCCN1CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the (S)-4-(4-chloro-phenyl)-3,3-dimethyl-piperidin-4-ol (5.50 g, 22.94 mmol) in acetonitrile (200 mL) and water (50 mL) was added potassium carbonate (7.17 g, 51.9 mmol) followed by solid 1-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-ethanone (6.30 g, 17.3 mmol). The heterogeneous mixture was stirred at room temperature 4 hours, warmed to 50° C. and stirred 13 hours. The mixture was cooled to room temperature and acetonitrile was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (750 mL) and the extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (3:1 ethyl acetate:hexanes) to afford (S)-1-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3, 3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-ethanone as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Br[CH2:12][C:13]#[CH:14].C1(C)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:14][C:13]#[CH:12]
Reactant: COCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOCCOCCOC
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution under N2 of 2-(2-methoxy-ethoxy)ethanol (4.9 ml, 41.61 mmoles) in dry THF (50 ml) was portionwise added at room temperature under stirring with 60% NaH in oil (1.66 g, 41.61 mmoles). The mixture was stirred for 30 minutes then dropped into a solution of 80% 3-bromo-propyne in toluene (5.1 ml, 45.77 mmoles), and stirred for 1 hour, then diluted with ethyl ether, thrice washed with water, anhydrified over Na2SO4 and dried to give 5 g of the title compound as an oil (yield: 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH2:15][NH2:16])[N:12]=[CH:11][C:10]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1.[C:29]1([C@@H:35]2[CH2:37][C@H:36]2[N:38]=[C:39]=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH2:15][NH:16][C:39]([NH:38][CH:36]2[CH2:37][CH:35]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:40])[N:12]=[CH:11][C:10]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1
Reactant: CC(C)c1nnc2ccc(-c3cnn(CCN)c3-c3ccc(F)cc3F)nn12
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3cnn(CCNC(=O)NC4CC4c4ccccc4)c3-c3ccc(F)cc3F)nn12
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
The 2-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)ethanamine (0.075 g, 0.20 mmol) was dissolved in DCM (4 mL) then trans-2-phenylcyclopropyl isocyanate (0.033 g, 0.21 mmol) was added. The mixture was stirred for about 10 min then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (0.065 g, 61%): LC/MS (Table 1, Method a) Rt=2.34 min; MS m/z: 543.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.C(OCC)(=O)C.O>CO.[Fe]>[NH2:19][C:14]1[C:15]([C:17]#[N:18])=[N:16][C:11]([S:10][C:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[C:7]([Cl:9])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1N

Procedure:
10 ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3-nitropicolinonitrile (3.4 g, 0.01 mol) in 50 ml of methanol under stirring. The reaction medium is refluxed, added together with 1.68 g (0.03 mol) of iron and stirred for 10 minutes. After returning to room temperature, the reaction mixture is added together with 100 ml of ethyl acetate and 50 ml of water. The pH is adjusted to 10 using 30% soda solution and the organic phase is extracted and then dried on anhydrous sodium sulfate before being concentrated. The residue is purified by silica gel chromatography (ethyl acetate/petroleum ether) to yield, after concentration of the fractions, 2.82 g (91%) of a yellow solid.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>CN1CCCC1=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(CCc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.19 g (1.0 eq) of 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid 0.19 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.24 g (5.0 eq) of N-methylmorpholine, and 20 mL of N-methylpyrrolidone is stirred under nitrogen and at room temperature for one hour and 0.23 g (2.0 eq) of diethyl L-glutamate hydrochloride is added. The mixture is stirred for an additional 24 hours under nitrogen and the solvents then removed by evaporation. Chloroform is added and this mixture is then washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed, eluting with 2% methanol/chloroform to yield diethyl N-(4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate. m.p. >250° C.; 1H NMR (CDCl3) delta 8.63 (s, 1H), 8.33 (s, 1H), 7.74 (d, J=8.11 Hz, 2H, Ar), 7.21 (d, J=8.11 Hz, 2H, Ar), 7.19 (d, J=6.9 Hz, 1H, NH), 4.77-4.84 (m, 1H-CH--), 4.24 (q, J=7.4 Hz, 2H, CO2CH2), 4.12 (q, J=7.4 Hz, 2H, COOCH), 3.05 (s, 4H, 2° aliphatic), 1.97-2.61 (m, 4H, 2° aliphatic), 1.34 (s, 9H, t-butyl), 1.29 (t, J=8.4 Hz, 3H, --CH3), 1.22 (t, J=8.4 Hz, 3H, --CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[C:11]([C:16]([OH:18])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>ClCCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:23][CH2:20][CH2:21][N:22]2[C:16](=[O:18])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(Cc1cccnc1C(=O)O)c1ccc(F)cc1
Solvent: CO
Solvent: ClCCCl
Product: O=C1c2ncccc2CC2(c3ccc(F)cc3)NCCN12
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 3-[2-(4-fluorophenyl)-2-oxoethyl]pyridine-2-carboxylic acid (1.5 g, 5.8 mmol) in 1,2-dichloroethane (100 mL) was added ethylenediamine (8 mL, 120 mmol) and the resulting solution heated at reflux for 1 hour. The resulting suspension was then allowed to cool to room temperature before being concentrated in vacuo to yield a thick, orange gum. The gum was suspended in methanol with the aid of sonication and filtered. The filtrate was adsorbed onto silica and purified by flash chromatography (5 to 7.5% methanol-dichloromethane) to yield 10a-(4-fluorophenyl)-2,3,10,10a-tetrahydroimidazo[2,1-g][1,7]naphthyridin-5(1H)-one as a pale yellow solid (1.1 g, 67% yield). ESI-MI m/z [M+H]+ 284.04. 1H NMR (400 MHz, CDCl3) δ 8.66 (brd, J=4.7 Hz, 1H), 7.36 (brd, J=7.7 Hz, 1H), 7.30 (dd, J=8.9, 5.2 Hz, 2H), 7.23 (dd, J=7.7, 4.7 Hz, 1H), 6.89 (t, J=8.7 Hz, 2H), 4.02-3.89 (m, 1H), 3.70-3.60 (m, 1H), 3.47 (d, J=15.2 Hz, 1H), 3.42 (d, J=15.2 Hz, 1H), 3.35 (ddd, J=12.4, 7.9, 2.8 Hz, 1H), 2.86-2.74 (m, 1H), 2.49 (brs, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]2[S:13](=[O:15])(=[O:14])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[C:11](=[O:27])[CH2:10]2)=[CH:6][CH:5]=1.[C:30]([NH:37][CH2:38][C:39](O)=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:33]([O:32][C:30](=[O:31])[NH:37][CH2:38][C:39](=[O:40])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:10][C:11](=[O:27])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[S:13]2(=[O:14])=[O:15])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(CN)cc3)S2(=O)=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title B compound, 5-(4-aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride (89 mg, 0.20 mmol) is suspended in dry THF (10 mL) and N-Boc glycine (42 mg, 0.24 mmol) is added. EDCl (58 mg, 0.30 mmol) is added, followed by TEA (61 mg, 0.60 mmol). The mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is chromatographed on silica gel using CH2Cl2→g 3% MeOH in CH2Cl2 as the eluent to afford ({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamic acid t-butyl ester as a white solid: [M+NH4]+=580.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20]([CH2:23][O:24][NH2:25])([OH:22])=[O:21].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:25][O:24][CH2:23][C:20]([OH:22])=[O:21])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NOCC(=O)O
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CON=C1CCCc2cc(OCCn3ccnc3)ccc21
Yield: 43.6 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10 mL of pyridine was treated with 1.02 g (9.3 mmol) of carboxymethoxyamine×0.5 HCl and the solution heated at reflux for 2 days. The solution was diluted with H2O and extracted with EtOAc. On standing, the aqueous phase deposited a solid which was collected and dried. There was obtained 0.56 g (43% yield) of the product as a white solid, mp 193-195° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 330 (M+H+).
Reaction SMILES: F[C:2]1C=C(OC(CCCCCCCCC)=O)C=C[C:3]=1C(O)=O.C(OC1C=CC(C2C=CC(C([O:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([O:55][CH:56]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:57]([F:60])([F:59])[F:58])=[O:54])=[C:49](F)[CH:48]=3)=O)=CC=2)=CC=1)CCCCCCC>O1CCCC1>[OH:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]([O:55][CH:56]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:2][CH3:3])[C:57]([F:58])([F:59])[F:60])=[O:54])=[CH:51][CH:52]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Reactant: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: C1CCOC1
Product: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
To a solution of the 2-fluoro-4-n-nonylcarbonyloxybenzoic acid (0.3 g) obtained in (3) above and the 1,1,1-trifluoro-2-decyl 4-hydroxybenzoate (0.3 g) obtained in (2) above in tetrahydrofuran (about 30 ml) were added dicyclohexylcarbodiimide (0.25 g) and dimethylaminopyridine (0.02 g). The solution was stirred at room temperature for about 20 hours. The solution was distilled to remove the solvent. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrone magnesium sulfate and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl acetate=20/1) to obtain the titled compound (0.21 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[CH:14]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[CH:14]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1-c1cnc2c(c1)c(-c1ccccc1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cnc2[nH]cc(-c3ccccc3)c2c1
Temperature: 80 °C

Procedure:
To a solution of 3-phenyl-5-(2-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (374 mg, 0.85 mmol) in methanol (2.3 ml) is added NaOH (260 μl of 2 N solution in water, 0.51 mmol). The mixture is heated at 80° C. for 1 hour and then cooled at room temperature.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH:21]=1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1cccnc1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 25.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (95 mg, yield: 25.9%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[CH:29]=[C:30]([O:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]=3[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=2)=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[CH2:37]([O:36][C:30]1[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])=[CH:14][CH:15]=3)[C:28]=2[CH:29]=1)[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.7 %

Procedure:
A solution of 2.3 g p-toluenesulfonic acid chloride in 5 ml absolute dichloromethane is added dropwise to a solution of 3.5 g (−)-cis-6-(4-Aminophenyl)-8,9-diethoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at room temperature for a further 3 h. After the evaporation of the solvents, the residue is extracted with dilute sodium hydroxide solution and dichloromethane. The organic phase is then washed with water, dried over sodium sulfate and concentrated. 5.4 g of the title compound are obtained as rough product, which is recrystallised twice in ethyl acetate/methanol. Yield: 4.3 g yellowish crystalls. M.p. 267-268° C.