Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][NH:3]1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Product: COC(=O)c1cnc(Cl)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the product from part 3 (12.5 g) in 50 ml of POCl3 is stirred at 100° C. for about two hours then cooled and concentrated under vacuum. The residue is dissolved in 300 ml of CHCl3, and the resulting solution is washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and then concentrated to give the title compound, m.p. 53-55° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:17]2[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A mixture of 4-nitrobenzaldehyde (6.612 g, 43.8 mmol) and (2R,6S)-2,6-dimethylpiperazine (5 g, 43.8 mmol) in 1,2-DCE (100 mL) was stirred at room temperature for 2 h. Sodium tri(acetoxy)borohydride (13.92 g, 65.7 mmol) was added and the reaction was stirred at room temperature over-weekend. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The aqueous wash was extracted with 10% MeOH/DCM and the combined organics were dried and concentrated. Column chromatography eluting with 0-10% MeOH/DCM gave the title compound as a cream solid (4.278 g). δH (CDCl3, 400 MHz) 8.18 (2H, d), 7.51 (2H, d), 3.57 (2H, s), 2.97 (2H, m), 2.72 (2H, m), 1.72 (2H, m), 1.06 (6H, d). MS (ES+): MH+ 250.2.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[CH:26]=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:31])=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36].O>O1CCOCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:35](=[O:36])[C:34]([Cl:39])([Cl:38])[Cl:33])=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:30])=[O:31])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution containing 0.77 g (0.0017 mol) of 2-morpholin-4-yl-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzenesulfonamide of Step B and 0.62 g (0.0034 mol) of trichloroacetyl chloride in 50 mL of 1,4-dioxane was heated under reflux for 3 hrours. The solution was allowed to cool to room temperature and then poured into 750 mL of water with stirring. The solid was collected, washed and dries to provide the title compound (0.88 g), m.p. 165-167° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[Cu][C:12]#[N:13].[C-]#N.[K+]>CN(C=O)C>[C:12]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)cs1
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cs1
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a solution of 3.82 g (17.3 mmol) methyl 4-bromothiophene-2-carboxylate (as prepared in the previous step) in 10 mL of anhyd DMF was added 3.10 g (34.6 mmol) of copper (I) cyanide. The mixture was heated to reflux with stirring for 18 h, cooled and poured into 100 mL of 10% (w/v) KCN. The mixture was extracted with EtOAc (3×60 mL) and the combined extracts were washed with 150 mL each of water and brine. The dark solution was dried over Na2SO4, treated with decolorizing carbon, filtered and the resulting colorless solution concentrated in vacuo. The resulting light yellow solid was recrystallized from MeOH to afford the title compound as a cream-colored solid (1.67 g, 58%). 1H-NMR (300 MHz, CDCl3) δ8.09 (d, 1H, J=1.4 Hz), 7.93 (d, 1H, J=1.4 Hz), and 3.93 (s, 3H). IR (film): 2235 and 1712 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:6]=12.[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:24][CH:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)=[O:15])[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 40 (shown in the scheme 7, 600 mg, 1.54 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography, eluents EtOAc and EtOAc/MeOH (10:1), to afford the title compound 289 (160mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H) (found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 89.4 %

Procedure:
A mixture of 6.4 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.0 g of 2-(dimethylamino)ethyl chloride hydrochloride, 5.8 g of potassium carbonate and 150 ml of acetone is treated in the same manner as described in Example 1. The crude product thus obtained as recrystallized from a mixture of ethyl acetate and n-hexane. 6.93 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)c1c[nH]c2cc3c(cc2c1=O)OCO3
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature was maintained at 80°-90° for an additional two hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[OH:17])=[N:2]1.C(OCC)C>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16](=[O:17])[CH3:18])=[N:2]1
Reactant: CC(O)c1ccccc1-c1noc2ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
In 46 ml of dry pyridine was dissolved 4.6 g of 2-(1,2-benzisoxazol-3-yl)-α-methyl-benzenemethanol. Under an atmosphere of nitrogen, 4.6 g of chromium trioxide was slowly added at room temperature. After stirring at room temperature for 4 h, 200 ml of diethyl ether were added to the reaction mixture. The precipitates were filtered off and washed with diethyl ether. The filtrate was washed with 5 portions of 100 ml of 2N aqueous hydrochloric acid and 2 portions of 200 ml of water, dried over magnesium sulphate and evaporated to dryness to afford 4.5 g of 1-[2-(1,2-benzisoxazol-3-yl)phenyl)-ethanone, melting at 108° C.
Reaction SMILES: [H+].[B-](F)(F)(F)[F:3].N[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@@H:17]2[O:37][C@H:36]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:18]2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([NH2:47])[N:9]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:20]([O:19][C@H:18]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:37][C@H:17]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:8]([F:3])=[N:9][C:10]=2[NH2:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h

Procedure:
HBF4 (48%) (150 ml) was added to a solution (5°) of 2-amino-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)adenine (III, 4.6 g, 8.4 mmol) in CHCl3 (60 ml). The resulting mixture was cooled to -10° before a solution of N--NO2 (17 g, 25 mmol) in 4 ml of H2O was added dropwise with stirring. After the addition was complete, the mixture was stirred an additional 40 min. at -10° to -5° before it was diluted with CHCl3 (75 ml), cooled to -20°, and neutralized (pH 5-6) with 50% NaOH. The CHCl3 layer was separated, washed with H2O, dried (MgSO4), and evaporated to dryness in vacuo. The residue, primarily a mixture of II and 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2,6-difluoropurine, identified by TLC (1:1 CHCl3 -EtOAc), was dissolved in absolute EtOH, and the solution was saturated at 5° with dry NH3. After refrigeration overnight, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in CHCl3 (25 ml), and the solution was filtered through dry Celite to remove inorganic salts. The filtrate was adsorbed on a silica gel column (2.6×35 cm, packed and equilibrated with CHCl3). The column was eluted with 1:1 CHCl3 -EtOAc. The fractions containing II were combined and evaporated to dryness in vacuo, and the residue was recrystallized from C6H6 (40 ml); yield 1.7 g (36%); mp 157°-159°; λmax (mμ), pH 1, 7, 13, and EtOH--261, 272 (sh); vmax (cm-1) 3350, 3320, 3150 (NH), 2940, 2920, 2910, 2860 (CH), 1665, 1610, 1575 (NH, C=C, C=N), 1110, 1100, 1085, 1060 (COC), 730 (phenyl).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)c(N)c1
Reaction time: 70 h
Yield: 69.4 %

Procedure:
A stirred mixture of methyl 4-hydroxy-3-nitrobenzoate (3.22 g, 0.0163 mol) and 5% Pd—C (12.9 g) in MeOH (30mL) was hydrogenated under an atmospheric pressure for 70 hr at room temp. Insoluble catalyst was removed, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica-gel with EtOH—CHCl3 (1:20, v/v) as eluent to afford 1.89 g (69%) methyl 3-amino-4-hydroxybenzoate as a pale brown syrup.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].CO.[H][H]>[Ni].O>[CH:12]([S:11][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:8])([CH3:14])[CH3:13]
Reactant: CC(C)Sc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)Sc1ccccc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
34.7 g of 2-chloro-6-nitrophenyl-isopropylsulfane, 140.0 g of methanol and 1 g of Raney nickel 55, as the catalyst (water-moist), were initially introduced into a 0.3 l steel autoclave. After the air had been displaced with nitrogen and hydrogen, hydrogen was forced in at room temperature up to a pressure of 80 bar, while stirring the mixture, a slight increase in temperature already being observed. The mixture was heated to 60° C., while continuing to stir and keep the hydrogen pressure constant. After about 2 hours, the uptake of hydrogen had ended. The mixture was then cooled to room temperature, the hydrogen was let down, the catalyst was filtered off with suction and washed with methanol and the combined filtrates were concentrated. Crude yield: 29.6 g of 2-amino-6-chlorophenyl-isopropylsulfane with a purity of 99.5% (GC), corresponding to 97.5% of theory. The content of 2-isopropylmercaptoaniline formed by hydrogenating dehalogenation was only 0.1%. Furthermore, only 0.1% of impurities due to 3-chloroaniline, formed by hydrogenating desulfurization, were found.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:33][CH:32]([NH:34][C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:31][CH:32]([NH:34][C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:33]3)=[O:29])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (640 mg, 0.976 mmol) (obtained as described in Reference Example 75(1)) in anhydrous tetrahydrofuran (32 ml) was added a solution of acetic acid (67 μl, 1.17 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.17 ml, 1.17 mmol) in an ice bath and the mixture was stirred in an ice bath for 1.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5→9:1) as the eluant to afford 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (360 mg, yield 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[CH:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:12]=2[CH:13]=1
Reactant: CN(CCc1ccc(N)cc1)Cc1cc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.76 g, 6.6 mmole) was added dropwise to a solution of N-methyl-N-(5-aminobenzofur-2-ylmethyl)-4-aminophenethylamine (see Preparation 3--0.9 g, 3.0 mmole) in pyridine (25 ml) and the mixture was stirred at room temperature for 18 hours. The solvent was then evaporated and the residue diluted with aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated, and the residue was purified by chromatography on silica eluting with ethyl acetate. The product-containing fractions were combined, evaporated and the resulting solid was recrystallised from ethyl acetate/methanol to give the title compound, yield 0.35 g, m.p. 177°-179°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][CH2:23][O:24][CH3:25]>O1CCCC1.CCOCC>[CH3:25][O:24][CH2:23][CH2:22][C:4]1([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:6][CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1
Reactant: COC(=O)C1CCCC(C)(C)C1
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCC1(C(=O)OC)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 146B (0.60 g) in tetrahydrofuran (5 mL) was added to lithium diisopropylamide (2.0 M, 2.10 mL) at −78° C. After stirring for 30 minutes, 1-bromo-2-methoxyethane (0.64 g) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ether (75 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 1-20% ethyl acetate in hexanes provided the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 316 mg, 7.91 mmol) in DMF (10 mL) was added in portions 4-hydroxybenzonitrile (856 mg, 7.19 mmol). After stirring for 15 min at rt, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.00 g, 7.19 mmol) was added, and the reaction mixture was stirred at 80° C. for 1 h and at 150° C. for a further 1 h. After cooling to rt, water was added, and the mixture was stirred for 15 min. The solid was filtered off, water was added again, and the mixture was stirred for further 15 min and then filtered again. This procedure was repeated once again. Finally, the solids obtained were dried in vacuo to give the title compound (1.47 g, 59%): ES-MS m/z 317, HPLC RT (Method F) 2.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6]C1C=CC(C(Cl)=O)=CC=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([C:19]4[C:2]([Cl:1])=[C:3]([CH:16]=[C:17]([Cl:20])[CH:18]=4)[C:4]([NH2:6])=[O:5])=[CH:19][CH:2]=3)=[O:5])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: c1ccncc1
Product: NC(=O)c1cc(Cl)cc(-c2ccc(C(=O)N3CCc4cncnc4-c4ccccc43)cc2)c1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,5-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido-[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2 g (11.6 mmol) 5-chloro-2-nitro-phenylamine, 2.14 g (11.6 mmol) piperazine-1-carboxylic acid tert-butyl ester and 1.3 g (11.6 mmol) 1,4-diazo-bicyclo[2.2.2]octane in 20 ml DMSO was heated to 150° C. for 16 h. The mixture was poured onto 200 ml water and extracted with 250 ml ethyl acetate. The emulsion was filtered through decalite and the aqueous phase was extracted with 2×200 ml. The combined organic phases were washed with 2×100 ml water, dried with MgSO4 and evaporated to dryness. The residue was purified with column chromatography on silica eluting with ethyl acetate/hexane to yield the title compound as a yellow solid. MS(ISP): 321.2 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:9][CH2:8][C:3]([C:4]([CH3:5])=[O:6])([CH3:7])[CH2:2][O:1]2)=[CH:14][CH:13]=1
Reactant: CC(=O)C(C)(CO)CO
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COC(c2ccc(N(C)C)cc2)OC1

Procedure:
3,3-bis(Hydroxymethyl)butanone (29.0 g), p-dimethylaminobenzaldehyde (29.8 g), toluene-p-sulphonic acid (250 mg) and toluene (140 ml) were heated under reflux in a Dean and Stark water trap until the theoretical amount of water had separated. The solution was concentrated in vacuo, the crude residue was washed with 8% aqueous sodium bicarbonate solution (100 ml) and crystallised from petroleum ether (b.p. 80°-100°)/ethyl acetate as a crystalline solid m.p.118°-120° (Cis-trans 96:4).