Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:38]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.1 g. (6 mmoles) of 4,5-bis-(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 1.3 g. (12 mmoles) of potassium tert-butoxide in 60 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 1.7 g. of benzoyl chloride in 15 ml. of toluene was then added and the reaction mixture stirred overnight at room temperature. The mixture was diluted with methylene chloride, which was washed with 10% aqueous sodium bicarbonate solution, dried and evaporated. The residue was purified by chromatography on Fisher 100-200 mesh silica gel (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to afford 1.8 g. of colorless crystals, m.p. 105.5°-106° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([OH:17])[CH:13]=[CH:12]2)(=O)=O.[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].[F-].[Cs+]>COCCOC.CO.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>[OH:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: O=S(=O)(Oc1cccc2ccc(O)nc12)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc3ccc(O)nc23)cc1

Procedure:
A mixture of Example 336A (2.93 g, 10 mmol), 4-(methoxycarbonyl)phenylboronic acid (1.80 g, 10 mmol), Pd(Ph3P)4 (0.346 g, 0.3 mmol), and CsF(1.52 g, 10 mmol) in DME (60 mL) and methanol (30 mL) was heated to reflux for 18 hours and concentrated. The concentrate was dissolved in water (50 mL) and ethyl acetate (300 mL) and the organic phase was washed with water (2×50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 280, 278 (M+H)+, (M−H)−.
Reaction SMILES: [C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)(C)C#N)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(C)(C)C#N)ccc1C(=O)O
Temperature: 65 °C
Yield: 78 %

Procedure:
Methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (340 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (98 mg, 4.1 mmol) was added and reaction mixture was heated at 65° C. for 1 hour. The crude material was diluted with 10 mL of water and was extracted two times with ether. The ether extracts were discarded and the aqueous layer was made acidic with 4M HCl. The product was then extracted into ethyl acetate, dried over sodium sulfate, filtered, and evaporated to dryness to yield 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid (78%) as a pale yellow solid. ESI-MS m/z calc 235.1, found 236.1 (M+1)+. Retention time: 1.29 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=O)[NH:9][C:7](=O)[C:6]2=[CH:12][CH:13]=1.B.CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:12][CH:13]=1)[CH2:7][NH:9][CH2:10]2
Reactant: COc1ccc2c(c1)C(=O)NC2=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CNC2
Temperature: 0 °C
Yield: 46.6 %

Procedure:
A stirred solution of 4-methoxyphthalimide (21.3 g, 0.12 mol) in anhydrous tetrahydrofuran (425 ml) at 0° C. was treated dropwise with a solution of borane in tetrahydrofuran (1M, 340 ml, 0.34 mol) and the resulting mixture was stirred and held at reflux for 16 hours. The mixture was cooled to 0° C., methanol (150 ml) was added dropwise followed by 5M hydrochloric acid (150 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo, the mixture was diluted with water (750 ml) and was extracted with dichloromethane (3×750 ml). The aqueous layer was basified to pH 12 or above by the addition of 5M sodium hydroxide, extracted with dichloromethane (3×750 ml) and the combined extracts were evaporated to dryness in vacuo to afford 5-methoxyisoindoline (8.34 g, 47%) as a brown oil. 1H NMR (DMSO-d6) 7.13 (1H, d), 6.84 (1H, d), 6.74 (1H, dd), 4.05 (2H, s), 4.01 (2H, s), 3.73 (3H, s). MS: [M+H]+ 150.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([F:32])[CH2:26]1)[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][C@@H:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][C@@H:27]4[F:32])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CCN1CC[C@@H](N)[C@@H](F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCN1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@@H](F)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), (3S,4R)-1-ethyl-3-fluoro-piperidin-4-ylamine (dihydrochloride salt) (6.30 g, 29.0 mmol), diisopropylethylamine (21.0 ml, 120 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 14 h. The mixture was cooled to 25° C. and was stirred at that temperature for 4 h. The resulting yellow precipitate was collected by vacuum filtration, washed with Et2O (1×30 ml), and air-dried to give (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((3S,4R)-1-ethyl-3-fluoro-piperidin-4-yl)-amine (11.5 g, 90% over 3 steps) as a yellow solid. LCMS (Method G, ESI): RT=0.69 min, m+H=448.3; 1H NMR (400 MHz, CDCl3) δ 9.35 (d, J=8.4 Hz, 1H), 9.12 (s, 1H), 8.29-8.11 (m, 2H), 7.69-7.59 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.26 (s, 1H), 6.65 (d, J=4.2 Hz, 1H), 4.86 (d, J=48.6 Hz, 1H), 4.28-4.05 (m, 1H), 3.27-3.13 (m, 1H), 2.97-2.87 (m, 1H), 2.52 (q, J=7.2 Hz, 2H), 2.49-2.37 (m, 1H), 2.29 (t, J=10.0 Hz, 1H), 2.15-1.98 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1.Br[CH2:29][C:30](=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:16][CH2:15]2)[C:11]=1[CH3:12]
Reactant: CCC(=O)CBr
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)CN1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine hydrochloride salt (42 mg, 0.1 mmol), 1-bromo-butan-2-one (0.1 mmol, 1 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL) and then stirred at room temperature overnight. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C93 as an oil (39.6 mg, 88%). Exact mass calculated for C21H26FN3O5S 451.2, found 452.3 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]2[CH:51]=[CH:50][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]3=[O:49])=[CH:21][CH:20]=2)[CH3:12])=[CH:7][N:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=NOCCO)c1ccc(OC(C)C)nc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(OC(C)C)nc1
Yield: 81.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.02 g of 2-[1-(2-isopropoxy-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 32), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.24 g of triphenylphosphine and 784 mg of diethyl azodicarboxylate, 2.39 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[C:32]([CH2:33][O:34][CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([NH:26][CH2:24][CH3:25])=[C:32]([CH2:33][O:34][CH3:35])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COC
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1COC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 205.1.1, 0.067 mmol) and ethyl-[3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 206.1.1) to give the title compound as a yellow solid. (HPLC: tR 2.20 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.22-8.18 (m, 1H), 8.13 (s, 1H), 8.05-8.00 (m, 1H), 7.88-7.84 (m, 1H), 7.45-7.40 (m, 2H), 6.09 (t, 1H), 4.38-4.30 (m, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 3.33 (s, 3H), 1.95 (s, 3H), 1.14 (t, 3H))
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[CH2:24][CH2:25][CH3:26]
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (300 mg, 1.00 mmol) prepared in Example (8b) in tetrahydrofuran (20 mL) were added butyraldehyde (107 mg, 1.49 mmol), sodium triacetoxyborohydride (420 mg, 1.99 mmol) and acetic acid (60 mg, 0.99 mmol) in that order, the mixture was stirred at room temperature for 13 hours and 30 minutes. After the reaction completed, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 270 mg of 1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[CH2:24]([OH:27])[CH2:25][OH:26].[H-].[Na+]>CN(C=O)C>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:26][CH2:25][CH2:24][OH:27])=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: OCCO
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccc(OCCO)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.3 %

Procedure:
A solution of 6-fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (30.0 mg, 0.095 mmol) and ethylene glycol (59.1 mg, 0.951 mmol) in anhydrous DMF (1 mL) was treated with NaH (40.0 mg, 0.951 mmol). The bubbling reaction was stirred for 15 minutes at room temperature, then heated at 80° C. for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3×50 mL). The combined organics were washed with water (3×15 mL), dried (MgSO4), and concentrated to produce an oil. The oil was purified via Biotage chromatography using a gradient of 2.5%-5% MeOH/CH2Cl2 as eluent to yield 12 mg (35%) of 1-hydroxy-6-(2-hydroxyethoxy)-3-morpholin-4-yl-xanthen-9-one as a white powder. Rf=0.55 (5% MeOH/CH2Cl2). 1H NMR (DMSO-d6, 400 MHz) δ: 12.91 (s, 1H), 8.05 (d, 1H), 7.10 (m, 2H), 6.48 (s, 1H), 6.34 (s, 1H), 4.98 (m, 1H), 4.18 (t, 2H), 3.78 (t, 2H), 3.70 (m, 4H), 3.38 (m, 4H). LRMS (APCI, positive): Da/e 358.4 (m+1).
Reaction SMILES: S(O)(O)(=O)=O.NO.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=1)=O.[N:19]1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=1)#[N:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: c1ccncc1
Agent: NO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(B(O)O)cc1
Yield: 144.1 %

Procedure:
17 g (100 mmol) of hydroxylamine sulfate were added at 70° C. to 15 g (100 mmol) of 4-formylphenylboronic acid, 10 g of water, 5 g (60 mmol) of pyridine and 200 ml of toluene. The mixture was then refluxed on a water separator. When all the water had been removed, the pyridinium salts were separated off, giving 12.7 g (87%) of 4-cyanophenylboronic acid.
Reaction SMILES: O1CCCC1.C(O)C.[N+](C1C=CC(C([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:24][O:25][N+:26]([O-:28])=[O:27])=O)=CC=1)([O-])=O.[OH-].[Na+]>C(=O)(O)[O-].[Na+]>[N+:26]([O-:28])([O:25][CH2:24][CH:23]([O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:21][CH2:20][CH2:19][OH:18])=[O:27]
Reactant: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a tetrahydrofuran/ethanol 1:1 (12 mL) solution of 5,6-bis(nitrooxy)hexyl 4-nitrobenzoate (2.5 g, 6.70 mmol) at 0° C. was added 2.5 N sodium hydroxide (6.5 mL) dropwise. The solution was stirred at room temperature for 3 hours. The solution was diluted with a solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo, affording the title compound. 1H NMR (300 MHz, CDCl3) δ: 5.45-5.38 (m, 1H), 4.94 (dd, 1H), 4.73-4.67 (m, 1H), 4.43 (t, 1H), 3.40-3.36 (m, 2H), 1.75-1.68 (m, 2H), 1.43-1.36 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]1([C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:17])([CH3:16])[C:14]1([CH3:19])[CH3:18])=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([C:13]2([C:20]([O:22][CH3:23])=[O:21])[C:14]([CH3:18])([CH3:19])[C:15]2([CH3:16])[CH3:17])=[O:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C1(C(=O)Cl)C(C)(C)C1(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(C(=O)Nc2ccc(Br)cc2C)C(C)(C)C1(C)C
Yield: 60 %

Procedure:
4-Bromo-2-methylaniline (2.09 grams, 0.01 mole) and methyl 1-chlorocarbonyl-2,2,3,3-tetramethylcyclopropanecarboxylate (2.45 grams, 0.01 mole), prepared in Part B, were reacted in the presence of 1.13 grams (0.01 mole) of triethylamine in 70 milliliters of benzene solution in a manner similar to that described in Example I to give 2.13 grams (0.006 mole) of methyl 1-(4-bromo-2-methylphenylamino-carbonyl)-2,2,3,3-tetramethylcyclopropaneca rboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Cl)cc1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 4-chlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.04 (s, 1H), 7.76 (d, 1H, J=5.0 Hz), 7.51 (d, 1H, J=5.0 Hz), 7.29-7.36 (m, 4H), 4.51 (s, 2H). [M+H] calc'd for C13H11ClN2O2, 263, 265. found 263, 265.
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].[Cl:12]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:11][C:3]([CH2:1][CH3:2])=[N:4][C:5]=12
Reactant: CCc1nc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(Cl)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
2-Ethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 4.00 g, 27.2 mmol) was dissolved in chloroform (45 mL), and the solution was added with m-chloroperbenzoic acid (5.18 g, 29.9 mmol) followed by stirring at room temperature for 5 hr. The reaction mixture was concentrated, added with ethyl acetate and water, and partitioned between ethyl acetate and water. The aqueous layer was concentrated and the residue was dissolved in chloroform (8 mL). Phosphorus oxychloride (24 mL, 257 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured onto ice, neutralized with aqueous ammonia, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and the precipitated solid was collected by filtration to give the title compound (3.32 g, 67%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1.O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:34])[CH3:35])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)c[nH]1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(SC)cn1Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g de 2-butyl 4-(methylthio) 1H-imidazole is dissolved in 120 cm3 of THF. Then 1.55 g of sodium hydride at 50% dispersion in oil is added slowly to the orange-coloured solution obtained. The temperature increases to 25° C. Agitation is carried out for 30 minutes at this temperature then 14 g of 4'-bromomethyl N-[(dimethylamino) methylene](1,1'-biphenyl) 2-sulphonamide is introduced. Agitation is carried out at ambient temperature until evolution ends, i.e. for approximately 3 hours, followed by taking up in water, extracting with ethyl acetate, separating by chromatography on silica eluting with ethyl acetate then impasting in iso ether, filtering and drying. In this way 9.35 g of expected product (colourless crystals) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Br:11])=[C:4]([C:6]([Br:10])=[CH:7][C:8]=1[Br:9])[NH2:5].[Br:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Br:12][CH2:13][C:14]([NH:5][C:4]1[C:6]([Br:10])=[CH:7][C:8]([Br:9])=[C:2]([CH3:1])[C:3]=1[Br:11])=[O:15]
Reactant: Cc1c(Br)cc(Br)c(N)c1Br
Reactant: O=C(Cl)CBr
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc(Br)c(NC(=O)CBr)c1Br
Temperature: 100 °C
Yield: 48.8 %

Procedure:
To a solution of 3-methyl-2,4,6-tribromoaniline (4.36 g, 12.7 mmol) in toluene (40 mL) at room temperature was added bromoacetyl chloride (1.20 mL, 14.6 mmol) and the slurry heated to 100° C. for 24 h. The reaction was cooled, filtered, washed with and placed on a high vacuum pump to provide 2.88 g (49%) of the title compound as a white solid. mp 207-209° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.52 (s, 3H) 4.07 (s, 2H) 8.05 (s, 1H) 10.38 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 24.2, 28.6, 121.3, 123.4, 127.2, 134.3, 134.9, 137.6, 164.4; MS (DCI/NH3) m/e 482 (M+NH4+); Anal. calcd for C9H7Br4NO: C, 23.26; H, 1.52; N, 3.01. Found: C, 23.30; H, 1.45; N, 2.94.