Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)[C:21]([CH2:31][O:32][CH2:33][CH3:34])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.CO>C(#N)C.[OH-].[Pd+2].[OH-]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:31][O:32][CH2:33][CH3:34])[N:22]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 24 h

Procedure:
Palladium hydroxide (Pearlman's catalyst) (20% palladium w/w on carbon, 900 mg) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine (9.00 g, 19.46 mmol, 1 eq), prepared as described in Example 152, in acetonitrile (300 mL) and methanol (300 mL) in a sealed vessel and the reaction mixture was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 24 hours. The crude reaction mixture was filtered through a layer of CELITE filter aid and the filtrate was concentrated under reduced pressure and triturated with acetonitrile. The resulting crystalline material was collected by filtration and washed with acetonitrile to afford 3.66 of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid. Additional product (0.36 g) was isolated from the filtrate of the initial trituration by concentration under reduced pressure, trituration with acetonitrile, and filtration for a total yield of 4.02 g of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol, isolated as an off-white solid, mp 240-242° C. 1H-NMR (300 MHz, DMSO) δ 9.51 (br s, 1H), 7.96 (d, J=8.9 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.9, 2.6 Hz, 1H), 6.46 (br s, 2H), 4.92-4.60 (m, 4H), 4.57-4.45 (m, 1H), 4.18 (dd, J=8.6, 6.4 Hz, 1H), 3.83 (dd, J=8.6, 6.5 Hz, 1H), 3.54 (q, J=7.0 Hz, 2H), 1.34 (s, 3H), 1.19 (s, 3H), 1.15 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, DMSO) δ 156.41, 152.0, 148.1, 147.2, 133.9, 124.4, 121.7, 111.7, 109.7, 109.0, 107.9, 74.4, 66.0, 65.2, 64.3, 47.6, 26.2, 24.9, 14.8; MS (APCI) m/z 373.0 (M+H)+; Anal. calcd for C19H24N4O4: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.12; H, 6.53; N, 14.98.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[C:15]([CH3:26])[CH:14]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.C1([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=2B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:15]1[CH:14]=[C:13]([O:12][CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:34]3[CH:33]=[CH:38][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=3)[N:7]=2)[CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Reactant: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 21.8 %

Procedure:
A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)butyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.12 mmol) in DME (0.5 mL) was treated with phenyl 4-(triflouromethyl)benzeneboronic acid (23 mg, 0.12 mmol) followed by Pd(PPh3)4 (14 mg, 0.01 mmol) and a solution of Na2CO3 (38 mg, 0.36 mmol) in water (0.5 mL), and the resulting mixture was heated at 70° C. for 18 hours under nitrogen. The solvent was then removed under vacuum and the resulting mixture acidified with aqueous HCl (2M) and then partitioned between water and EtOAc, the layers separated and the organic layer reduced to an oil. Purification by mass directed auto-prep HPLC afforded the title compound (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:30].FC(F)(F)C(O)=O.[SH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].[OH-].[Na+]>C(Cl)Cl>[C:41]([CH2:40][CH2:39][S:38][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:30])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:43])=[O:42]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Temperature: 0 °C
Yield: 52.4 %

Procedure:
While stirring under ice cooling, 1 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine was added to a mixed solution of 8 ml of trifluoroacetic acid and 6 ml of methylene chloride, then 0.25 g of 3-mercaptopropionic acid was added to the solution and the mixture was stirred under ice cooling for 2 hours. After completion of the reaction, 180 ml of ice water was added the mixture, the mixture was adjusted to about pH 3 with a 1N-sodium hydroxide aqueous solution and then the aqueous layer was extracted with 200 ml of methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate and the residue obtained by removing the solvent under reduced pressure was recrystallized from ethyl acetate to obtain 0.63 g of the title compound as white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.S(Cl)([Cl:28])=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol (40.24 g, 114.6 mmol) in dichloromethane (350 mL) was cooled to 0° C. Thionyl chloride (12.5 mL, 172 mmol) was added dropwise, and the reaction was heated at reflux for one hour. The reaction was cooled to 0° C., and water (200 mL) was slowly added followed by solid sodium bicarbonate until the pH of the solution was basic. The solvent was partially removed under reduced pressure, and the aqueous solution was extracted with ethyl acetate (500 mL). The combined organic solutions washed with saturated aqueous sodium bicarbonate (3×50 mL), water (1×50 mL), and brine (2×20 mL), and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a yellow oil, which crystallized overnight. The solid was dried for one hour in a vacuum oven at 70° C. to provide 40.1 g of (5-chloropentyl)-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[CH2:3][OH:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(F)(F)CCC1C=CC=CC=1>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)([F:12])[F:1]
Reactant: Cc1cccc(C(F)(F)CO)c1
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Product: Cc1cccc(C(F)(F)COCCCCCCBr)c1
Yield: 100 %

Procedure:
Obtained from Intermediate 29 (5.55 g, 32.2 mmol) by the procedure described in Intermediate 3. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 10:1) as eluent gave the title compound (10.99 g, 100%) as oil.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(=O)(O)[O-].[Na+]>[C:22]([O:4][C:3]1[CH:2]=[CH:1][C:17]2[CH2:16][C@H:15]3[N:18]([CH3:19])[CH2:20][CH2:21][C@:7]45[C:6]=2[C:5]=1[O:9][C@H:8]4[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]35)(=[O:24])[CH3:23]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 100 %

Procedure:
A modification of the method of Welsh (1954) was utilized. Morphine free base (1 am, 3.50 mmol) was suspended in saturated sodium bicarbonate solution (50 ml), and to the stirred suspension was added drop-wise an excess of acetic anhydride (1 ml, 10.6 mmol). The resulting solution was extracted with chloroform (6×10 ml) and the combined organic extracts were dried over anhydrous magnesium sulfate. Following filtration the solvent was removed by rotary evaporation under reduced pressure to afford 1.14 gm (100%) of 3O-acetylmorphine as a glassy white amorphous solid. The product was homogeneous by TLC (CHCl3:MeOH (9:1), Rf=0.85). Elemental Analysis Calcd. for C19H21NO4: C, 69.73, H, 6.42; N, 4.28. Found: C, 69.71;, H,6.40; N, 4.32.)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:13]1[NH:14][C:15](=[O:25])[C:16]([OH:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)([O:9][CH2:10][CH2:11]O)[CH2:7][Cl:8])(=[O:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].CCN(CC)CC>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1([CH2:7][Cl:8])[C:13]2=[N:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([O:24][S:27]([CH3:26])(=[O:29])=[O:28])[C:15](=[O:25])[N:14]2[CH2:11][CH2:10][O:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(CCl)(COC(C)=O)OCCO)[nH]c(=O)c1O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)CCOC2(CCl)COC(C)=O
Temperature: 60 °C

Procedure:
A solution of ethyl 2-(3-acetoxy-1-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (2.322 g, 6.13 mmol) in tetrahydrofuran (100 mL) was treated with methane sulfonylchloride (2.11 g, 18.4 mmol) and Et3N (2.25 g, 22 mmol) and then heated (60° C., oil bath) for 3 hrs. Solvent was removed in-vacuo and the crude product was dissolved in ethyl acetate (100 mL), then washed with water (2×50 mL). The organic solution was dried (Na2SO4), filtered and concentrated in-vacuo to give the title compound as a viscous amber oil which was used immediately in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:32][C@H:31]1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[O:29])([CH3:26])([CH3:25])[CH3:24].[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@@H:33]3[CH2:34][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@H:31]([C:48](=[O:52])[N:49]([CH3:50])[CH3:51])[CH2:32]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethylformamide (8 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (0.489 g; prepared as described in the starting materials for Example 22), (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine (0.678 g) and cesium fluoride (0.697 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol and adsorbed onto silica. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated. The residue was re-purified by column chromatography eluting with increasingly polar mixtures of ethyl acetate/methanol (100/0 to 92/8). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless gum which crystallised on standing (0.36 g); 1H NMR Spectrum: (DMSO d6 @ 373K) 1.41 (s, 9H), 1.99 (m, 1H), 2.92-3.03 (m, 7H); 3.44 (m, 1H), 3.96 (s 3H), 4.14 (m, 1H), 4.70 (t, 1H), 5.10 (m, 1H), 7.22-7.30 (m, 2H), 7.44 (t, 1H), 7.62 (t, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 560.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].O.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To 0.83 g (3.2 mmol) of (1-benzyloxycarbonylpiperidin-4-yl)isocyanate from Procedure 1, Step A in 10 mL was added 16 mL (32 mmol) of 2 M dimethylamine in THF. The reaction was stirred under nitrogen at rt for 24 h and then poured into water containing 20 mL of 2N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 0.95 g of the crude title compound which can be used directly in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][C:3]=1[C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][C:3]=1[C:19]([C:20](=[CH:29][N:30]([CH3:32])[CH3:31])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:26]
Reactant: CCOC(=O)CC(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
A solution of 3.88 g (crude) of ethyl 3-[2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)phenyl]-3-oxopropionate and 1.22 g (0.10 mmol) of dimethylformamide dimethyl acetal in 10 ml of toluene were heated to reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Purification on silica gel (petroleum ether) (45-70° C.)/ethyl acetate, 8 minutes isocratic 35% ethyl acetate, then to 60% ethyl acetate in 7 minutes, flow rate 400 ml/minute) afforded 3.59 g (82% over the two stages) of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CN(C=O)C>[C:19]([C:18]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:17]=1[N:5]([O:4][CH3:3])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, N-methoxy-p-toluenesulfonamide (0.45 g (2.20 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2-chloro-5-nitrobenzonitrile (0.37 g (2.03 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.48 g (68%) of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH3:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[S:12](N)(N)(=[O:14])=[O:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[CH2:9][N:10]([CH3:11])[S:12](=[O:14])(=[O:13])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1c(N)cccc1Br
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CN1Cc2c(Br)cccc2NS1(=O)=O

Procedure:
To a solution of 3-bromo-2-methylaminomethyl-phenylamine from step 3 of Example 3 (2.615 g, 12.2 mmol) in pyridine (50 ml) was added sulfamide (3.5 g, 36.4 mmol). The solution was heated under reflux overnight, and the cooled reaction mixture was partitioned between 2N HCl water solution and ethyl acetate. The organic layer was washed with 2N HCl solution, water, brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine 2,2-dioxide as a white solid. (2.32 g, 69%) MS: (M+H)+277.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:30][C:31]1[CH:32]=[C:33]([C:43](=[O:45])[CH3:44])[CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:40]1[CH2:39][CH2:38][N:37]([C:36]2[CH:35]=[CH:34][C:33]([C:43](=[O:45])[CH3:44])=[CH:32][C:31]=2[F:30])[CH2:42][CH2:41]1)=[O:6]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 2-Chloro-5-methanesulfonyl-benzoic acid (200 mg, 0.852 mmol) in DMF (3 ml) was added dropwise 1,1′-Carbonyldiimidazole (142 mg, 0.852 mmol). When the CO2 evolution ceased, the mixture was heated to 50° C. for 15 minutes. The mixture was cooled to room temperature. 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (189 mg, 0.852 mmol) was added portionwise. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Heptane/AcOEt 0%-50% (15 minutes) to provide the title compound (185 mg, 49%) as a white solid, MS (m/e): 439.1 (M+H+, 100%).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][C:34]([N:37]([CH3:38])[CH3:39])=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(N(C)C)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4ccc(N(C)C)cc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.1 mg, 0.12 mmol) prepared in Example 41 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (19 mg, 39%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH3:12])=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][CH3:12])=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CNc1ncc(Br)n2ccnc12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ncc(-c2ccc(F)cc2)n2ccnc12
Temperature: 170 °C

Procedure:
To a solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (intermediate O) (68 mg, 0.3 mmol) in DMF (4 ml) and water (2 ml) was added 4-fluorobenzene boronic acid (84 mg, 0.6 mmol), K2CO3 (165 mg 1.2 mmol), and Pd(PPh3)4 (35 mg, 0.1 eq). The mixture was heated at 170° C. in microwave for 6 min. The mixture was purified on a silica gel column to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:26]([N:29](CC2C=CC(OC)=CC=2OC)[C:30]2[S:34][N:33]=[CH:32][N:31]=2)(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][N:23]=[N:22][CH:21]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:26]([NH:29][C:30]2[S:34][N:33]=[CH:32][N:31]=2)(=[O:27])=[O:28])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][N:23]=[N:22][CH:21]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Cc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)benzyl]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 34, 54 mg, 0.083 mmol) was dissolved in dichloromethane (0.75 mL) and cooled to 0° C. Trifluoroacetic acid (32 μL, 0.41 mmol) was added as a solution in dichloromethane (0.25 mL) and the reaction stirred for 2 hours warming slowly to room temperature. The solvent was removed in vacuo and the residue re-dissolved in methanol. Once again the solvent was removed in vacuo. The material was suspended in methanol and filtered through Celite™. The reaction mixture was concentrated in vacuo and purified by the basic preparative HPLC method to afford the title compound.