Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(CCC(O)c2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(4-methoxy-phenyl)-propan-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:23])=O>>[Cl:23][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCO
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCl
Temperature: 80 °C
Yield: 4805.9 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 5-[(3-nitroquinolin-4-yl)amino]pentan-1-ol (5.0 g, 18.16 mmol), and thionyl chloride (40.78 g, 0.34 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a 20 homogeneous solution that was maintained at 80° C. for 1 hour at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting oil stirred in water made basic (pH 10) with solid sodium carbonate. The resulting solid was collected by filtration to afford N-(5-chloropentyl)-3-nitroquinolin-4-amine (4.80 g, 16.34 mmol) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2ncccc2F)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Nc2ncccc2F)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
The solution of 3-fluoro-N-(4-methoxyphenyl)pyridin-2-amine (0.50 g, 0.002 mol) in DCM (20 mL) was cooled to −40° C. and to it was added boron tribromide (1.14 g, 0.0045 mol) dropwise under nitrogen over 30 mins. The reaction mixture was stirred at −40° C. for 1 h then at RT for another 2 h. The reaction mixture was cooled at 0° C. and saturated sodium bicarbonate was added. After stirring for 30 mins, the reaction was extracted with ethyl acetate (20×3 mL). Combined organic extracts were dried over sodium sulfate and concentrated to give the desired product which was used directly in the next step. MS (ESI, pos. ion) m/z: 205.19 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2ON2C3C=CC=CC=3N=N2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2On2nnc3ccccc32)cc1
Reactant: NCc1ccc(F)cc1
Product: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2NCc2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(benzotriazol-1-yloxy)-6-chloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (0.348 g, 0.82 mmol) and 4-fluorobenzylamine (1.0 mL, 8.75 mmol) was stirred at 60° C. under N2 for 30 min, cooled to RT, and purified by flash column chromatography. The desired compound was obtained as a solid. MS (ES+) 413.0 (M+H)+. Calc'd for C22H22ClFN4O-412.89.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])=[CH:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:30][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 47115.7 %

Procedure:
To a stirred solution of 3β-hydroxyandrost-4-en-17-one (0.81 g) in CH2Cl2 (7.4 mL) cooled at 0° C., a solution of mCPBA (0.77 mg) in CH2Cl2 (13.6 mL) was added dropwise. After 0.5 h at 0° C. and 0.5 h at room temperature, a 10% aqueous solution of Na2SO3 was added. The mixture was neutralized by addition of 5% NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give 3β-hydroxy-5α,6α-epoxyandrostane-17-one (0.64 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (1H, d), 3.52 (1H, m), 2.87 (1H, d), 2.44-0.56 (19H, m), 1.00 (3H, s), 0.72 (3H, s).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[C:11]1([S:17]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(On1nnc2ccccc21)c1ccccc1
Yield: 85.5 %

Procedure:
In 1 N aqueous sodium hydroxide (49 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (6.6 g) (pH 6.8). To the solution is added dropwise benzenesulfonyl chloride (8.8 g) with stirring under ice-cooling and the mixture is stirred for 1 hour. The reaction mixture is extracted with ethyl acetate and the extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The crystalline residue is cracked well in n-hexane and separated by filtration and dried to give 1-benzenesulfonyloxy-1,2,3-benzotriazole (11.5 g), melting point: 83°-84° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:27].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:27][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:41])([F:40])[F:42]
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (100 mg, 0.27 mmol) in anhydrous DMF(15 mL) under a N2 atmosphere containing, at 0° C., sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol) was added. The mixture was allowed to stir at 0° C. for 30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O (1×15 mL), brine (1×15 mL), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to yield {4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone as off-white crystals.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C(#N)C.C(Cl)(Cl)Cl>[CH3:16][N:17]([CH3:19])[CH:18]=[N:2][S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc2ccncc2s1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2ccncc2s1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a partial suspension of 2-sulfamoylthieno[2,3-c]pyridine (1.81 g, 8.5 mmol) in acetonitrile (20 ml), under a nitrogen atmosphere, was added dropwise dimethylformamide dimethyl acetal (1.3 ml, 9.7 mmol). After 2 hours, the mixture was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 2.2 g of product. This material was recrystallized from ethyl acetate to give 2.05 g (90% yield); m.p. 169°-171° C. Analysis calculated for C10H11N3O2S2 : N, 15.60; C, 44.59, H, 4.12. Found: N, 15.79; C, 44.95; H, 4.08.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21]
Reactant: O=N[O-]
Reactant: c1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccccc2)nc2ncccn12
Temperature: 5 °C
Yield: 65.3 %

Procedure:
A mixture of 20 g of 2-phenylimidazo(1,2-a)pyrimidine, 200 ml of glacial acetic acid and 20 ml of water is warmed with stirring until the solids are completely dissolved. The solution is next cooled to 5° C. in an ice/salt bath. A solution of 15 g of NaNO2 in 50 ml of water is added dropwise to the cooled acetic acid solution while the solution is kept between 0°-5° C. throughout the addition of NaNO2 solution and three hours thereafter. The reaction mixture is further stirred for 12 more hours at room temperature. The green precipitate is filtered and washed thoroughly with water on a glass filter. The residue is recrystallized once from 2-propanol to yield about 15 g of 3-nitroso-2-phenylimidazo(1,2-a)pyrimidine, m.p. 223°-225° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.C(N(CC)C(C)C)(C)C.[C:27]1([S:37]([Cl:40])(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[ClH:40].[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][S:37]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCCCN1CCc2ccccc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCCCCN1CCc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A solution of 2-(4-aminobutyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (272 mg, 1 mmol), N,N-diisopropylethylamine (517 mg, 4 mmol) in CH2Cl2 (10 mL), was added naphtalene-1-sulfonyl chloride (238 mg, 1.05 mmol) and was stirred overnight at room temperature. The resulting solution was washed with water (3×15 mL) and dried over Na2SO4, and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). A 2.8 M solution of hydrogen chloride in ethanol (0.40 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (310 mg, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Product: Oc1ccc2c(c1)CN(Cc1ccc(Cl)cc1)CC2
Reaction time: 8 h
Yield: 65.8 %

Procedure:
2.9 g of 7-hydroxyisoquinoline are heated under reflux for 8 hours with 3.5 g of 4-chlorobenzyl chloride in 30 ml of ethanol. After standing overnight, 5.7 g of the isoquinolinium salt crystallize out (melting point: 273°-274°). This salt is dissolved in 200 ml of methanol/water 9:1 and, with cooling, 6 g of sodium borohydride are added. After evolution of hydrogen has ended, the mixture is heated under reflux for 15 minutes. It is then concentrated to 1/3 of its volume, and this is poured into 200 ml of water, ammonium chloride is added to saturation, and the solid material which has precipitated out is filtered off. Recrystallization from ethanol gives 3.6 g of colorless crystals (67% of theory), melting point: 177°-178°.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.C(OCC)(=O)C>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: COC(=O)CN1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
To a stirred suspension of methyl 2-(piperazin-1-yl)acetate dihydrochloride (0.67 g, 2.92 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.15 g, 1.07 mmol). The resulting mixture was stirred at rt for 10 min. Then 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.40 g, 1.33 mmol) was added as a solid. The reaction was heated at 90° C. for 4.5 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) followed by trituration with diethyl ether to give methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.357 g, 61%) as a light yellow solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (br s, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.63-7.71 (m, 1H), 6.80-6.86 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.77 (s, 3H), 3.67-3.73 (m, 4H), 3.34 (s, 2H), 2.73-2.79 (m, 4H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[CH2:1]([NH:8][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
0.28 ml (2.52 mmol) of benzylamine is added to a solution of 150 mg (0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 159 mg (74.4% of theory) of the title compound are obtained and reacted further without further purification. LC-MS (Method 3): Rt=3.83 min.; m/z=369 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:33](N)([NH2:36])(=[O:35])=[O:34]>N1C=CC=CC=1.CO>[CH3:32][C:27]1[C:26]([C:13]2[C:14]3[O:19][CH2:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:16]4[C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:3][CH2:2]5)=[N:9][C:10]([C:15]=34)=[CH:11][CH:12]=2)=[C:30]([CH3:31])[O:29][N:28]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCN(S(N)(=O)=O)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 120 °C
Yield: 77 %

Procedure:
(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.8 mg, 0.013 mmol) and sulfamide (7.8 mg, 0.081 mmol) were dissolved in pyridine (0.71 mL) and the solution was heated at 120° C. for 3 min in a microwave. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (5.1 mg, 74%). LCMS calc. for C24H27N7O4S (M+H)+: m/z=510.2. found: 509.7.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[CH2:8]1[O:9][C:10]2[CH:11]=[CH:12][C:4]([CH2:3][O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]=2[O:7]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCOCc1ccc2c(c1)OCO2
Yield: 24.1 %

Procedure:
60% Sodium hydride (0.6 g) was suspended in dimethylformamide (10 ml), and piperonyl alcohol (1.5 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane(1.8 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 0.6 g of 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]1[O:13][CH2:12]1>CO>[OH:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C1CO1
Solvent: CO
Product: OCCN1CCC2(CC1)OCCO2
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To 23 parts of 1,4-dioxa-8-azaspiro[4.5]decane in 300 parts by volume of methanol is added 15 parts of ethylene oxide in methanol. The mixture is stirred at -20° C. for 3 hours and allowed to warm to room temperature. The solvent is removed under reduced pressure and the residue distilled to afford N-hydroxyethyl-1,4-dioxa-8-azaspiro[4.5]-decane. The corresponding tosylate is formed by reacting 16 parts of the alcohol in 75 parts of dry pyridine with 21 parts of p-toluenesulfonylchloride. The mixture is stirred at 5° C. overnight and then poured into 300 parts by volume of ice water. The resulting solid is collected by filtration to afford the tosylate.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:15]([Cl:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1ccccc1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCN(C(=O)Cl)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 4.05 g (24.8 mmole) of N-Pentylaniline (from Step A) in 45 ml of toluene an 8.96 ml (24.8 mmole) of 2.77N NaOH were mechanically stirred at -5° C., and 25.7 ml (49.6 mmole) of 1.93M phosgene in toluene was added dropwise over 30 minutes while maintaining -5°. After half the phosgene solution had been added, the rate of addition was increased easily. After stirring at -5° for an additional 30 minutes, the phases were separated and the toluene layer was dried over 10 g of solid sodium chloride. Concentration gave 5.5 g (98%) of dark yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:22][CH:21]=1>C(Cl)Cl>[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:30])=[O:31])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)c2nsnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c3nsnc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-aminobenzoate (412 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (39C) (633 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product 39D, which was confirmed by LCMS, and used in the next reaction without further purification. 1H NMR (CHLOROFORM-d) δ: 8.33 (dd, J=8.0, 4.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.35-7.30 (m, 1H), 7.12 (d, J=8.7 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H). LC-MS: m/z 382.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2>>[CH3:27][C:21]1[N:22]=[C:23]2[C:18]([C:17]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccn2)c(N)c1
Product: Cc1ccc(Sc2ccccn2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product of Example 227b (60 mg, 0.278 mmol) was reacted with the product from Example 1d (50 mg, 0.278 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (24 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.44 (s, 3H), 2.73 (s, 3H), 6.45 (d, J=6.99 Hz, 1H), 7.02-7.12 (m, J=7.72, 1.10 Hz, 2H), 7.40-7.49 (m, 2H), 7.50-7.58 (m, J=1.84 Hz, 1H), 7.72 (dd, J=8.46, 3.31 Hz, 2H), 8.21-8.27 (m, J=2.94, 0.74 Hz, 1H), 8.38 (d, J=6.99 Hz, 1H), 8.85 (d, J=8.82 Hz, 1H), 10.99 (s, 1H); MS (ESI+) m/z 359 (M+H−TFA)+; (ESI−) m/z 357 (M−H−TFA)−.