Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:18])[C:15]#[C:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH2:14]([O:18][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1)[C:15]#[C:16][CH3:17]
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 186 mg of 4-chloro-6-phenylpyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(2-butynyloxy)-6-phenylpyrimidine (the present compound (38)), m.p.: 59.6° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:25])([CH3:24])[C:9]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:10]1([CH3:24])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[C:19]=2[C:20](=[O:21])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)=[CH:26][C:9]1=2
Reactant: CC1(C)c2cc(OCCBr)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)c2cc(OCCN3CCNC(=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To DMF solution (5 mL) of 8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one (44.9 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) were added at room temperature and stirred at 80° C. for 18 hr. After cooling to room temperature, the mixture was extracted with ethyl acetate washed with saturated brine. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by preparative TLC (dichloromethane/methanol) to obtain the title compound (white solid, 24 mg, 80%).
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Reactant: CC1CCCCN1CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CCCCN1CCNC(=O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of DCM containing 4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid (Intermediate 7, 1 eq.) was stirred at room temperature, DMAP (1.1 equivalent) and 2-(2-methylpiperidin-1-yl)ethanamine (1 eq.) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 eq.) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane gave, after evaporation, the expected product N-[2-(2-methylpiperidin-1-yl)ethyl]-4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (1) as a beige solid, in 80% yield (96% purity by HPLC). MS(ESI+): 442.7; MS(ESI−): 440.5.
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:12]([C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:14])[NH2:11]
Reactant: COC(=O)c1cccc(C(=O)NNC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(C(=O)NN)c1

Procedure:
14.6 g (44.5 mmol) methyl 3-[N′-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate are dissolved in 75 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is freed from solvent. White solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH2:23])=[O:22].[C:29](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:29][NH:23][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:27])([F:28])[F:16])[CH:19]=2)[CH2:12][CH:13]=1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CC=C(c2ccccn2)CC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 3-trifluoromethylbenzamide (95 mg, 0.5 mmol), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 15 mg (41%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 2H), 2.80 (t, J=4 Hz, 2H), 3.28 (m, 2H), 4.32 (d, J=5 Hz, 2H), 6.71 (m, 1H), 7.22 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.72 (m, 2H), 7.95 (d, J=6 Hz, 1H), 8.22 (m, 2H), 8.52 (m, 1H), 9.08 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 360 (M−H)+.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].[Cl:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[CH:14]([Cl:13])[CH3:18])=[CH:4][C:3]=2[O:2]1
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(Cl)C(=O)Nc1ccc2c(c1)OCO2

Procedure:
To a solution of 3,4-methylenedioxyaniline, (41.1 grams; 0.3 moles) in 270 cc of chloroform containing 90 cc of a 20% solution of sodium hydroxide, there is added 38.1 grams (0.3 moles) of 2-chloropropionyl chloride at about -10° C., while stirring vigorously and keeping the temperature not above -5° C. The mixture is stirred for an additional period of one hour, letting the temperature reach room temperature. The organic phase is then separated, washed with water, neutralized with potassium carbonate and allowed to evaporate at reduced pressure, thus obtaining a solid purplish residue from which the desired product is separated and recrystallized with diisopropyl ether with melting point 116°-117° C.; Rf=0.26 (toluene-AcOEt 9:1) I.R. (nujol) νmax: 3240, 1660, 1540, 1500, 1485, 1445, 1250, 1210, 1040, 930, 815, 790 cm-1 ; chlorine (Schoeninger) calc. % 15.6--Found % 15.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][CH:12]2[CH:10]([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1>O>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([CH:14]3[CH2:13][CH:12]4[CH:10]([CH2:11]4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 94.5 %

Procedure:
The title compound (D69) (270 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-4-carboxylic acid (D17) (200 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (157 mg). HOBT.H2O: 1.2 eq; Reaction time: 3 hrs.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[S:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:32].[OH-].[Na+].[CH3:35]I>C(Cl)Cl>[C:24](/[N:23]=[C:21](\[S:22][CH3:35])/[NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]2[C:3](=[O:32])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=3)[CH:14]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CI
Reactant: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NC(=O)c3ccccc3)ccc1C)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS/C(=N\C(=O)c1ccccc1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylcarbamothioyl)benzamide 20 (22 mg, 0.05 mmol) in DCM (0.5 mL) was added solid powder of NaOH (20 mg, 0.5 mmol) and MeI (7 mg, 0.05 mmol). The mixture was stirred at rt for 1 h to yield (Z)-methyl N′-benzoyl-N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)carbamimidothioate 21 after removal of DCM. The crude 21 was used without further purification. MS m/z 457.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1CC([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:44].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[Br:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])CC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
2,3,4,6-tetra-O-benzyl-D-galactopyranosylacetate (79.8 g) was dissolved in a mixture of toluene (160 ml) and isopropyl ether (520 ml), and the solution was cooled to −10 to 0° C. To this solution, an isopropyl ether solution (2.8 mmol/ml, about 100 ml) containing 2.0 equivalent volumes of HBr was added. After stirring for about 90 minutes at −10° C. to 0° C., an aqueous 5% sodium hydrogencarbonate solution was poured into the reaction solution, and excessive HBr was neutralized by stirring. The whole volume was transferred into a separation funnel for separation, then the water layer was discarded and washing was carried 2 times with an aqueous 10% sodium chloride solution. After concentration under vacuum, 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (GalBr) was obtained as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]#N)[CH:7]=[CH:6]2.[OH-:15].[Na+].C[OH:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(C#N)ccc2c1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc2nc(C(=O)O)ccc2c1
Temperature: 120 °C

Procedure:
6-Methoxy-quinoline-2-carbonitrile (9.3 g, 0.050 mol) in 96 ml methanol was treated with 240 ml of 20% NaOH and the mixture was heated to 120° C. in a sealed tube overnight. After cooling to 0° C. a precipitate appeared. The mixture was filtered to get a sodium salt that was suspended in water. HCl 25% was added until pH 3-4 to get the acid as a precipitate that was filtered and dried under vacuum. The mother liquid of the first filtration was acidified with HCl 25% until pH 3-4 until a precipitate appeared. The precipitate was filtered and the solid was washed in water and dried under vacuum to yield 9.6 g (86%) of the title compound as light brown solid. MS (m/e)=204 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[S:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([S:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CSc1ccc(C(=O)Cl)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.33 h

Procedure:
A solution of 4-amino-3,5-dichloropyridine (0.46 g) in dry dimethylformamide (20 mL) is treated with sodium hydride (0.23 g of a 60% dispersion in mineral oil; 2.8 mmol) and the mixture is stirred for 20 minutes. It is then treated with a solution of 3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g; that is prepared as described in Reference Example 20 in dimethylformamide (10 mL) and stirred at 60° C. for 2 hours. The solution is then concentrated and the resulting residue is partitioned between water (30 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (50 mL) and the combined organic layers are dried, concentrated, and subjected to flash chromatography on silica gel, eluting with a mixture of diethyl ether and pentane (1:1 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (0.7 g) in the form of a white crystalline solid, m.p. 157-159° C. [NMR (CDCl3):8.57 (s,2H), 7.69 (bs,1H), 7.47 (dd,1H,J=8 Hz,J=2 Hz), 7.43 (d,1H,J=2 Hz), 7.17 (d,1H,J=8 Hz), 4.95 (m,1H), 2.46 (s,3H), 1.98-1.6(m,8H): Elemental analysis: C,54.0; H,4.5; N,7.0; Cl,17.8%; calculated: C,54.4; H,4.6; N,7.05; Cl,17.85%].
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: BrCCc1ccccc1
Product: OCCN(CCO)CCc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]ethanol was prepared according to the general method as outlined in example 1. Starting from diethanolamine (6.0 g, 57), and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol). Yield 9 g, (90%); yellow oil; MS: 210 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18]C(=O)C)=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[OH:2][CH2:1][C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1ncc(OC(C)=O)c2c1[nH]c1ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ncc(O)c2c1[nH]c1ccccc12
Reaction time: 2 h

Procedure:
In 30 ml of dry tetrahydrofuran were dissolved 70 mg of the product of 1-carbomethoxy-4-acetoxy-9H-pyrido[3,4-b]indole. With ice-cooling, 4.0 ml of diisobutylaluminum hydride were added. The reaction mixture was allowed to stand for 2 hours, after which the unreacted reagent was decomposed with a small amount of water. The mixture was then extracted with ethyl acetate. The organic layers were pooled and concentrated and the resultant crystals were recrystallized from ethyl acetate to yield 16 mg of the title compound as white needles melting at 148°-150°0 C. (decomp.). The IR absorption spectrum shows absorption at 1680 cm-1 has disappeared. An intense absorption was observed at 1620 cm-1. Mol. wt. (based on mass spectrum) 214.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCCCc1c(O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CCCCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 81.5 %

Procedure:
3-Hydroxy-4-pentyl-5-phenylisoxazole (231 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (305 mg, 82%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16]3[C:19]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:20][N:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[C:14]2=[O:34])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].N.C(O)[CH2:38][OH:39]>>[OH:39][CH2:38][CH2:1][O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16]3[C:19]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:20][N:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[C:14]2=[O:34])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: OCCO
Reactant: COC(=O)C(C)(C)c1ccc(N2CCc3c(S(C)(=O)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Agent: N
Product: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(C(C)(C)C(=O)OCCO)cc2)CC3)cc1
Temperature: 80 °C
Yield: 33 %

Procedure:
2-{4-[3-Methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl]phenyl}-2-methylproprionic acid methyl ester (0.077 g, 0.15 mmol) was placed in a sealed tube containing 10% ammonia in ethylene glycol (3 mL) and heated 80° C. for 2 h. The reaction was cooled, quenched with H2O, extracted with EtOAc, and dried (MgSO4). Purification by chromatography on silica (1:1 hexanes/ethyl acetate) and then HPLC purification afforded 27 mg (33%) title compound. High Resolution Mass Spec (M+H)+ for C26H30N3O7S 528.1776.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:19][N+:20]([CH3:23])=CCl.[Cl-].[CH:25]([C:27]1OC(C(O)=O)=C[CH:28]=1)=O.Cl.Cl.C(N1CCNCC1)(C)C>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[O:16][C:15]([CH2:17][N:20]3[CH2:23][CH2:28][CH2:27][CH2:25][CH2:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)o2)CC1
Reactant: C[N+](C)=CCl
Agent: CC(C)N1CCNCC1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
5-(4-Isopropyl-piperazine-1-carbonyl)-furan-2-carbaldehyde. Vilsmeier reagent [(chloromethylene)dimethylammonium chloride, 0.820 g, 6.43 mmol] was suspended in DCM (30 mL) under nitrogen with stirring and cooled to 0° C. To this suspension was added 5-formyl-2-furancarboxylic acid (0.900 g, 6.43 mmol) and the combined mixture was stirred at 0° C. for 30 min. The mixture was warmed to rt, stirred for another 1.5 h, and filtered. The filtrate (containing 5-formyl-furan-2-carbonyl chloride) was set aside and maintained at 0° C. In a second flask, 1-isopropyl-piperizine dihydrochloride (1.28 g, 6.37 mmol) in DCM (15 mL) was cooled to 0° C. The solution was treated with TEA (2.250 g, 22.30 mmol) slowly and then was warmed to rt and stirred for 30 min. The reaction mixture was filtered and the filtrate was cooled to 0° C. This second filtrate was then treated dropwise with the previously prepared solution of 5-formyl-furan-2-carbonyl chloride at 0° C. The combined mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The reaction mixture was cooled to 0° C. and filtered, and the filtrate was washed with H2O (2×15 mL), 0.5 N NaOH (1×15 mL), and satd. aq. NaCl (1×15 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to yield the desired product (1.40 g, 87%).
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)NCC2
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3CCCCC3)=NN=2)N=1>>[CH2:17]([C:16]1[N:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:10][C:11]2=[N:14][N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cc1ccccc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(-c2cc3nnc(Cc4ccccc4)n3nc2-c2ccccc2Cl)cc1
Yield: 54.6 %

Procedure:
The title compound (20 mg, 54%) as a white powder was prepared from N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-phenylacetohydrazide (38 mg, 0.085 mmol) and triphenylphosphine dichloride (85 mg, 0.26 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 7B). HPLC/MS (method A): retention time=3.92 min. (M+H)+=431.2.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH:17]([NH2:19])[CH3:18])[CH3:14].[C:22]1([S:28]([CH2:31][CH2:32][NH:33][CH:34]([CH3:36])[CH3:35])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH:17]([NH:19][C:1](=[O:2])[N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][S:28]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:29])=[O:30])[CH3:18])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC(C)N
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CC(C)NC(=O)N(CCS(=O)(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A mixture of 12.15 g (0.075 mole) of 1,1'-carbonyl diimidazole and 7.50 g (0.0476 mole) of 1-diethylamino-2-propanamine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 12.26 g (0.054 mole) of N-[2-(phenylsulfonyl)ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the solution was refluxed for 19 hr. The solvent was removed in vacuo, and the residue was dissolved in a 50/50 mixture of methylene chloride and ether. The organic solution was extracted with several portions of water and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. Flash chromatography on silica gel (elution with methanol) gave 10.87 g (52.3 g) of clear colorless oil.