Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:30]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:11])[NH:9][N:10]=4)[N:7]=3)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Yield: 28.1 %

Procedure:
0.512 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 15 ml of n-butanol; 0.88 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.04 ml of N-ethyldiisopropylamine were added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the n-butanol was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.35 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]([OH:32])CO)=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:32])=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC(O)c1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.67 h

Procedure:
To a solution of 1-(3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethane-1,2-diol (Preparation 26B, 0.097 g, 0.223 mmol) in methanol (2 mL) at 0° C. was added a solution of sodium periodate (0.057 g, 0.268 mmol) in water (2 mL) dropwise. The white heterogeneous reaction mixture was stirred for 40 mins. at 0° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, concentrated, dried in vacuo to yield 3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde. LC/MS M+1=402.23.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.C(=O)([O-])[O-:17].[K+].[K+]>O>[OH:17][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CO)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of 4-bromomethyl-2-trifluoromethyl-benzoic acid (Example I7) (13.03 g) in water (200 ml) was added potassium carbonate (31.1 g). The reaction mixture was stirred at 95° C. for 1 hour. The reaction mixture was then allowed to cool to ambient temperature and was quenched by addition of aqueous hydrochloric acid (5M) (250 ml). The mixture was extracted with ethyl acetate (3×150 ml). The extracts were dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-hydroxymethyl-2-trifluoromethyl-benzoic acid (9.07 g) as a white crystalline powder. 1H-NMR (DMSO-d6, 400 MHz): 13.5 (br s, 1H), 7.81-7.66 (m, 3H), 5.53 (s, 1H), 4.62 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.Br[CH:11]([C:13]1[CH:14]=[C:15]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])[CH3:12]>>[CH3:33][N:32]([CH3:34])[C:30]([C:15]1[CH:16]=[C:17]2[C:22](=[C:13]([CH:11]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:12])[CH:14]=1)[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])=[O:31]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccccc1
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccccc1
Yield: 36.4 %

Procedure:
N-methylaniline (153 mg, 1.43 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (175 mg, 0.36 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(phenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (57 mg, 37%) as a white solid. Mass Spectrum: M+H+ 436. NMR Spectrum (DMSOd6): 1.57 (d, 3H), 2.65 (s, 3H), 2.90 (bs, 3H), 3.00 (bs, 3H), 3.16-3.22 (m, 2H), 3.23-3.31 (m partially hidden by H2O, 2H), 3.36-3.42 (m, 2H), 3.42-3.49 (m, 2H), 5.52 (s, 1H), 5.55 (q, 1H), 6.66 (t, 1H), 6.84 (d, 2H), 7.19 (t, 2H), 7.67 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1>O>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:9][CH3:10])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccc(OC)cc1
Solvent: O
Product: COc1ccc(OC)c(C(=O)Cc2cccc(Br)c2)c1
Temperature: 75 °C
Yield: 64.7 %

Procedure:
A mixture of 1,4-dimethoxybenzene (7.02 g, 50.8 mmol), 2-(3-bromophenyl)acetic acid (6.07 g, 28.2 mmol) and PPA (40 mL) was heated at 75° C. overnight and cooled to 50° C. Water (60 mL) was added, and the mixture was allowed to cool to room temperature. Additional water (100 mL) was added, and the mixture was extracted with DCM (2×200 mL). The organic phase was washed (100 mL H2O, 100 mL brine), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3-bromophenyl)-1-(2,5-dimethoxyphenyl)ethanone (6.12 g, 65%). 1H NMR (DMSO-d6): δ 7.45-7.41 (m, 2H), 7.29-7.24 (m, 1H), 7.23-7.19 (m, 1H), 7.13 (m, 2H), 7.11 (m, 1H), 4.29 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H); LCMS: 335.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH2:15])[CH2:5][CH2:4]1.C(OC([NH:23][C:24]1[S:28][C:27]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[N:26][C:25]=1[C:33](O)=[O:34])=O)(C)(C)C>>[NH2:23][C:24]1[S:28][C:27]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[N:26][C:25]=1[C:33]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCC2)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(CN)CC1
Product: Cn1ncc(NC(=O)c2nc(C3CCC3)sc2N)c1N1CCC(CN)CC1
Yield: 37 %

Procedure:
Following the procedure for Example 304 starting with 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-amine and 5-(tert-butoxycarbonylamino)-2-cyclobutylthiazole-4-carboxylic acid gave 305 as a white solid (44 mg, 37% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 7.45 (s, 1H), 3.75-3.62 (m, 4H), 3.23-3.07 (m, 4H), 2.60 (d, J=6.5 Hz, 2H), 2.47-2.29 (m, 4H), 2.17-2.01 (m, 1H), 2.00-1.90 (m, 1H), 1.84 (d, J=12.5 Hz, 2H), 1.56-1.43 (m, 1H), 1.36 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 390 (M+1)
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][OH:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1cc(Cl)cc(Cl)c1
Product: Clc1ccc(-c2cnc(OCc3cc(Cl)cc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3,5-dichlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(3,5-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=510 (M++1); Rt=5.12 min; 1H-NMR 400 MHz (CDCl3): δ 5.45 (s, 2H), 7.03 (d, J=9 Hz, 2H), 7.21-7.40 (m, 6H), 7.42 (d, J=2 Hz, 2H), 8.60 (s, 1H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ccccc1O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Methyl salicylate (149 g) was dissolved in acetic acid (900 mL), and bromine (50 mL) was added thereto. The mixture was stirred at room temperature for 21 hr. Water (10 L) was added to the reaction mixture, and the precipitated solid was collected by filtration, which was then recrystallized from methanol to give methyl 5-bromosalicylate (175 g) as white crystals.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[N:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]([O:4][CH2:5][Cl:6])=[O:3])[N:10]=1)=[O:3]
Reactant: OCc1cccc(CO)n1
Reactant: O=C(Cl)OCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCCl)OCc1cccc(COC(=O)OCCl)n1
Yield: 95 %

Procedure:
The reaction of the compound of the formula (II) with the compound of the formula (III) is carried out at a temperature between -30° C. and +10° C., preferably at about -5° C. This reaction will be described in detail hereinafter. At least 2 moles of chloromethyl chloroformate of the formula (III) [as calculated for 2,6-bis(hydroxymethyl)pyridine of the formula (II)] are dissolved in the desired solvent, preferably in chloroform, and a solution containing an organic base, preferably pyridine, in the same molar amount as the compound of the formula (III) in the same solvent is added at a temperature lower than 10° C., preferably at about -5° C., under stirring. The suspension obtained is stirred for about 20 minutes while care is taken to avoid any increase of the temperature. Then, 2,6-bis(hydroxymethyl)pyridine of the formula (II) is added to the above mixture at the same temperature at such a rate that the temperature reaches at most -5° C. The suspension is stirred for about 20 minutes to give a brown solution. After washing this solution with water and evaporation, a practically pure product with 95 to 97% of 2,6-bis(chloromethyloxy-carbonyloxymethyl)pyridine content is obtained. The product obtained after washing with water and making free of the solvent can be used without any purification or, if desired, may be further purified by chromatography on a silicagel column or on an other adsorbent, e.g. on a synthetic resin.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](I)=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH2:25][CH2:26][C:27]#[CH:28].C(OCC)(=O)C.O>CN(C)C=O.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][N:29]2[C:30](=[O:39])[C:31]3[C:32](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:34])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Nc2ncc(I)c(OCc3ccccc3)n2)c1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Nc2cccc(F)c2)nc1OCc1ccccc1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 4-(benzyloxy)-N-(3-fluorophenyl)-5-iodopyrimidin-2-amine (J2, 60 mg) and N-(4-pentynyl)phthalimide (76 mg) in N,N-dimethylformamide (500 μL), triethylamine (98 μL), copper(I) iodide (14 mg) and bis(triphenylphosphine)palladium(II) dichloride (10 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(5-(4-(benzyloxy)-2-((3-fluorophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (J3, 69 mg) as pale green solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 3 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl ]phenyl}acetamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.40 (s, 1H), 7.32–7.20 (m, 12H), 6.96 (t, 1H, J=4.8 Hz), 6.91 (d, 1H, J=7.6 Hz), 4.87 (s, 1H), 3.39 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.43 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.11 (s, 3H), 1.94 (m, 2H), 1.76 (d, 2H, J=12.4 Hz), 1.68 (t, 2H, J=6.8 Hz), 1.60 (dd, 2H, J=1.2, 8.4 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1>>[Br:17][C:18]1[S:19][C:20]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:21][CH:22]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1ccc(Br)s1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-bromo-5-(chloromethyl)thiophene: MS (ES) m/z 399 (M+1) and 401 (M+1, isotope).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O[CH:16]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:17]1[O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C[Si](N[Si](C)(C)C)(C)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:16]2[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:27]([O:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:17]2[O:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4]2=[N:8][C:9](=[O:11])[S:10][C:3]=12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1ncnc2[nH]c(=O)sc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: Nc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c2nc(=O)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Compound 30 (460 mg, 2.7 mmol) was glycosylated in the same manner as that used to prepare 6, requiring HMDS (30 mL), benzoyl-blocked sugar (5: 1.5 g, 3.0 mmol), and TMS-triflate (0.76 mL, 3.9 mmol). The reaction mixture was allowed to stir overnight at room temperature and was then worked up as described for 6 to yield 1.6 g (95%) of 31 isolated as a foam: UV λmaxMeOH) 230 nm (ε), 310 (): 1H NMR (DMSO-d6 9 δ6.45 (d, J=2.73 Hz, 1H, C1,H), 7.4-8.0 (m, 15 H, benzoyl aromatics), 8.59 (s, 1H, C5H), and other sugar protons C31H24N4O8S: C, 60.78: H, 3.95: N, 9.15: S, 5.23. Found:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=O.O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:16]=1
Reactant: O=Cc1ccccc1-c1cc2ccccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(Cc2cc3ccccc3o2)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A suspension of 2-benzofuranylphenyl-methanone (34.8 g, 0.157 mol), hydrazine monohydrate (31 mL, 0.639 mol) and diethylene glycol (72 mL) was heated to reflux for 10 min and cooled to room temperature. Potassium hydroxide (22.9 g, 0.408 mol) was added. The reaction mixture was heated in 130° C. oil bath for 1 h., cooled to room temperature and added to water. The oil was extracted with ether. Silica ge was added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed eluent: (petroleum ether) to provide the title compound as an oil (23.9 g, 90%): NMR (CDCl3); δ7.5-7.1 (m, 9 H), 6.38 (s, 1 H), 4.10 (s, 2 H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 87%), MS (ISP) m/z=423.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.5 mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (220 mg, 6.8 mmol) and stirred at RT for 10 min., followed by 4-(2-methyloxiran-2-yl)pyridine (1.08 g, 9 mmol) and stirred at RT for 16 h. The progress of reaction was monitored by TLC. The mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 8.70 (d, 2H), 7.90 (d, 2H), 7.40 (m, 1H), 7.0 (m, 2H), 6.0 (m, 1H), 4.80 (m, 1H), 4.60 (m, 2H), 4.25 (m, 2H), 3.80 (m, 2H), 2.90 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:22]=1)[C:7](=[O:21])[N:8](O)[C:9]3=[O:19].C1C(=O)N([Cl:30])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[C:6]2[C:5]3=[C:10]([CH:11]=[C:12]([Cl:30])[C:13]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:4]3[CH:3]=1)[C:9](=[O:19])[NH:8][C:7]2=[O:21]
Reactant: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)c2cc(Cl)c(N3CCCC3)c3cc(Br)cc1c23
Yield: 45.2 %

Procedure:
A mixture of 5-bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.42 mmol, from Example 59) and NCS (0.072 g, 0.54 mmol) in acetic acid (12 mL) was reacted at 100° C. for 3 hours. The reaction mixture was cooled and poured into water. The resulting precipitate was collected by filtration, washed with water, and dried to give 0.072 g of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19]O.Cl>N1C=CC=CC=1>[C:2]1([C:1]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:12])[O:13][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1onc(-c2ccccc2)c2ccccc12

Procedure:
A mixture of o-benzoyl benzoic acid (0.01 mol) and hydroxylamine hydrochloride (0.01 mol) is refluxed in pyridine (40 ml) for 3 hours, is cooled, and is poured over ice-cold dilute-HCl. The separated solid is filtered off, is dried and is crystallized from ethanol to give the title compound.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)(=[O:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NC1CCC1
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of N-cyclobutyl-2-nitrobenzenesulfonamide (7 g, 27.3 mmol) in methanol (100 mL) was added palladium on carbon (10%). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford the product 2-amino-N-cyclobutylbenzenesulfonamide (6 g, yield 97.1%). 1H NMR (400 MHz, CDCl3) δ ppm 7.68-7.71 (dd, 1H, J=1.6 Hz, 8.0 Hz), 7.27-7.33 (m, 1H), 6.74-6.82 (m, 2H), 5.30 (s, 1H), 5.08 (s, 2H), 3.70-3.73 (m, 1H), 1.96-2.04 (m, 2H), 1.67-1.75 (m, 2H), 1.48-1.62 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1>CS(C)=O>[NH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:21])(=[O:20])[NH2:22])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:3]([NH2:5])=[NH:2]
Reactant: NS(=O)(=O)c1ccc2ccnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1nccc2ccc(S(N)(=O)=O)cc12
Temperature: 60 °C
Yield: 85.5 %

Procedure:
Guanidine hydrochloride (42 mg, 0.44 mmol) was added in one portion to a suspension of NaH (13 mg, 80% dispersion by wt in mineral oil, 0.43 mmol) in DMSO (1.5 mL) and the mixture was heated at 60° C. under N2 for 30 min. 1-Chloro-7-isoquinolinesulphonamide (37 mg, 0.152 mmol) was added and the mixture heated at 100° C. for 24 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2—MeOH-0.880NH3 (97:3:0.3 to 90:10:1) as eluant to give the title compound (34 mg, 0.13 mmol) as an off-white solid.