Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:5])[C:15]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was washed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46°-50° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[CH3:26][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:35]3[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:39]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12]1[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=[C:14]([NH2:25])[N:13]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
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: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(CCN4CCOCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine (8.8 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (6.3 mg). LCMS (M+H)+: m/z=518.4.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]=1.[OH-].[Na+]>CO>[OH:25][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:15]=[CH:14]/[C:10]1[N:9]=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C#CCCC(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C#CCCC(=O)O)n1
Yield: 57.2 %

Procedure:
Under the conditions of example 2, 20 mg of 5-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyl}-4-pentynoic acid methyl ester in 1 ml of methanol is saponified with 2 ml of 1 n sodium hydroxide solution and worked up. 11 mg of the title compound is obtained as yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53].CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][C:5]([F:25])([F:24])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:15])([F:14])[F:16])[C:8]([NH:49][C@@H:50]([CH2:59][CH3:60])[CH:51]([OH:58])[C:52]([NH:54][CH:55]2[CH2:56][CH2:57]2)=[O:53])=[O:10])[CH2:2][CH2:3]1
Reactant: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: CC[C@H](N)C(O)C(=O)NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A solution of (S)-5-cyclopropyl-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-pentanoic acid (0.5 g; 1.35 mmol) in dry dichloromethane (16 mL) under nitrogen was treated with HOBt (228 mg; 1.49 mmol; 110 mol %), EDC hydrochloride (286 mg; 1.49 mmol; and (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (311 mg; 1.49 mmol; 110 mole %). N-methylmorpholine (NMM; 210 μL; 301 mg; 2.97 mmol; 220 mole %) was added and resulting mixture was stirred for 20 h at ambient temperature. The dichloromethane was removed by distillation and the residue partitioned between ethyl acetate (50 mL) and washed in sequence with 10% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous sodium chloride (20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 740 mg of the crude product which was chromatographed on silica gel (5 g), eluting with ethyl acetate/hexane, 1:2 followed by 1:1, to give 469 mg (66.2%) of (25)-5-cyclopropyl-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-yl)-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)pentanamide. LC-MS, positive ion mode: m/z=524 [M+H]+ (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. Nos. 7,488,848 and 7,893,112.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=CN(C)C.N1C2C(=CC=CC=2)C(=[O:40])NC=1>O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=[O:40]
Reactant: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Reactant: O=c1[nH]cnc2ccccc12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (1.38 g, 6.45 mmol) in water (6 mL) and tetrahydrofuran (6 mL) was added 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.70 g, 2.15 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ether. The filtrate was rendered basic by addition of saturated aqueous sodium bicarbonate and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over potassium carbonate, and concentrated. The residue was flash chromatographed on silica gel (1×3 inches) with elution proceeding as follows: 50% methylene chloride/hexane (400 mL), nil; (100 mL) and 50% ethyl acetate/hexane (150 mL), 0.51 g (82%) of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as about a 1:1 mixture of free aldehyde and hydrate which contained about 20% of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (from simple hydrolysis of the enamine; exists exclusively in its enolized form to take advantage of an internal hydrogen bond to N1 of the quinazolin-4-one). Identifying features of each of the components of this mixture can be observed in the NMR spectrum as defined in the table below:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:25])[N:5]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:6]2=[O:15].CN(CCN(C)C)C.[I:34]I>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][C:8]([I:34])=[C:7]2[C:3]=1[CH:4]([OH:25])[N:5]([C:16]([CH3:17])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:24])[C:6]2=[O:15]
Reactant: II
Reactant: COCOc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 96.1 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-5-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.01 g, 8.32 mmol) was dissolved in THF (110 mL), and the solution was treated with TMEDA (4.00 mL, 26.5 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 28.0 mL, 26.6 mmol) and iodine (2.53 g, 9.98 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (3.90 g, yield 96%).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12.[C:19]([C:22]1[CH:23]=[C:24]([NH:29]C(=O)C)[CH:25]=[CH:26][C:27]=1O)(=[O:21])[CH3:20].N1CCCC1.Cl>CO.C(O)C>[NH2:29][C:24]1[CH:25]=[CH:26][C:27]2[O:18][C:15]3([CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:2]5[C:3]([CH:6]=4)=[N:4][O:5][N:1]=5)[CH2:13][CH2:14]3)[CH2:20][C:19](=[O:21])[C:22]=2[CH:23]=1
Reactant: O=C1CCN(CCc2ccc3nonc3c2)CC1
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Agent: Cl
Solvent: CCO
Solvent: C1CCNC1
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Yield: 77.3 %

Procedure:
1-[2-(Benzofurazan-5-yl)ethyl]-4-piperidinone (0.98 g, 4 mmol), N-(3-acetyl-4-hydroxyphenyl)-acetamide (0.77 g, 4 mmol) and pyrrolidine (0.33 ml, 0.28 g, 4 mmol) in methanol (20 ml) were heated under reflux for 3 hours, cooled and the solvent was evaporated under reduced pressure. Water (50 ml) and aqueous sodium hydroxide (20%, 10 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid. Ethanol (40 ml) and aqueous HCl (6N, 40 ml) were added and the mixture was heated under reflux for 2 hours. The mixture was cooled and the ethanol was evaporated under reduced pressure. Water (40 ml) was added and the mixture was washed with ethyl acetate (50 ml). Aqueous sodium hydroxide (20%, 60 ml) was added slowly, with stirring and cooling, and the mixture was extracted with dichloromethane (3×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was triturated with ethyl acetate-hexane (1:1, 20 ml) and the solid was collected and dried in vacuo to give a yellow solid (1.17 g, 77%). A sample was recrystallized from chloroform-hexane to give the pyranone as a yellow solid, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[C:36]([CH3:38])[N:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1csc(Br)n1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-4-methyl-1,3-thiazole, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 240-241° C. (hexane-ethyl acetate).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:21]2[CH2:25][C@:24]3([CH3:30])[C@H:26]([OH:29])[CH2:27][CH2:28][N:23]3[C:22]2=[O:31])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:21]2[CH2:25][C@:24]3([CH3:30])[C:26](=[O:29])[CH2:27][CH2:28][N:23]3[C:22]2=[O:31])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(N2C[C@]3(C)[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(N2C[C@]3(C)C(=O)CCN3C2=O)ccc(C#N)c1Cl
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To a 2 M CH2Cl2 solution of oxalyl chloride (68 □L, 0.13 mmol) in CH2Cl2 (2 mL) at −78° C. was added DMSO (17 □L, 0.25 mmol). After 20 min, a solution of (7R,7aR)-2-chloro-4-(7-hydroxy-7a-methyl-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (58F) (17 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added. After an additional 20 min at −78° C., triethylamine (62 □L, 0.47 mmol) was added, the cold bath was removed, and the reaction mixture was stirred for 20 min. Water was added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 100×20 mm, eluting with 30-80% solvent B (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (6.3 mg) as a white solid. LC/MS m/z 629 [2M+23]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:20]([C:21]5[CH2:22][N:23]([CH3:26])[NH:24][CH:25]=5)=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]4=[N:16][CH:17]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>C1COCC1>[CH3:26][N:23]1[CH2:22][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([CH2:11][CH:8]4[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]4)[CH:13]=3)[N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:19]=2)=[CH:25][NH:24]1
Reactant: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC5(CC4)OCCO5)cc23)=CN1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN1CC(c2cn(COCC[Si](C)(C)C)c3ncc(CC4CCC(=O)CC4)cc23)=CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 87 (307 mg, 0.64 mmol) in THF (20 mL) was added 6.0 N aq. HCl solution (7 mL) and the reaction mixture was allowed to stir at r.t. for 1 h. Water (50 mL) was then added, and the mixture extracted with AcOEt (2×75 mL). The combined organic solutions were dried (MgSO4) and concentrated to afford 88 as a clear oil (261 mg, 0.59 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.99 (t, J=8.2 Hz, 2H), 1.49-1.62 (m, 2H), 2.07-2.16 (m, 2H), 2.31-2.49 (m, 5H), 2.82 (d, J=6.7 Hz, 2H), 3.65 (t, J=8.3 Hz, 2H), 4.07 (s, 3H), 5.77 (s, 2H), 7.49 (s, 1H), 7.69 (s, 1H), 7.83 (s, 1H), 7.92 (s, 1H), 8.27 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)N[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(Cl)(=[O:30])C.C[N:33]([CH:35]=O)[CH3:34]>>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[CH:14]([C:20](=[O:30])[CH3:21])[C:15]1[C:34]3[N:33]=[CH:35][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C1C2=C(CSc3cccnc32)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C

Procedure:
8-(tert-Butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (170 mg, 0.462 mmoL) in DMF (2 mL) was treated with NaH (60%, 37 mg, 0.925 mmoL) at 0° C. Acetyl chloride (52 mg, 0.693 mmoL) was added dropwise into the reaction 30 minutes later. The reaction mixture was than slowly warmed to room temperature over 2 hours. The reaction was quenched with saturated NH4Cl. The residue was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 5:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].C(Cl)(Cl)Cl.C(Cl)Cl.I[Si](C)(C)C>C(#N)C>[CH3:1][N:2]([C:3]([C:4]([F:7])([F:6])[F:5])=[O:8])[C:3]([C:4]([F:7])([F:6])[F:5])=[O:8]
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)C(F)(F)F)C(=O)C(F)(F)F

Procedure:
The compound of formula III is initially protected by reaction with a trimethylsilating agent such as N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in an inert solvent such as chloroform or methylene chloride. The resulting trimethylsilyl ester, in which all potentially reactive sites, such as amino, hydroxy, and carboxylic acid functions, are protected by trimethylsilyl groups, is then subjected to a reaction with iodotrimethylsilane at about 0° C. to room temperature, over a period of about twenty minutes to about two hours. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is dissolved in a suitable non-hydroxylic solvent such as acetonitrile. A small amount of tetrahydrofuran (THF) is introduced to decompose any residual traces of iodotrimethylsilane. The resulting protected iodo intermediate is then further reacted in situ with a protected form of the pipefarine derivative IV which is obtained from IV by treatment with a trimethylsilating agent such as MBTFA in a compatible solvent such as acetonitrile. The quaternization reaction is conducted at about room temperature over a period of about 30 minutes to 24 hours, preferably about 2 hours. Addition of a hydroxylic solvent such as methanol, with ice-cooling, then causes solvolysis of the trimethylsilyl protecting groups, and the quaternary iodide of formula IA precipitates. Further treatment under aqueous conditions with a base such as sodium bicarbonate or sodium hydroxide, or with sodium phosphate buffer, converts IA to the zwitterionic form I in which, depending upon the amount of base added, or the pH of the buffer, other acidic functions in the R3 and Q substituents can be converted to salts. ##STR29##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([Cl:31])[C:23]=1F>>[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([Cl:31])[C:23]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Product: COc1ccc(Cn2nc(C)c3c(Oc4c(Cl)cc([N+](=O)[O-])cc4Cl)ccnc32)cc1
Yield: 76.2 %

Procedure:
Prepared from 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in Example 5, Step B) and 1,3-dichloro-2-fluoro-5-nitrobenzene (0.117 g, 0.557 mmol), according to the procedure of Example 13, Step A. The crude product was purified Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to obtain the product (195 mg, 73%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.93 (d, J=5.5 Hz, 1H), 5.58 (s, 2H), 3.77 (s, 3H), 2.75 (s, 3H). LRMS (esi pos) m/e 460 (M+1).
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH3:21])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 75 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are introduced into 50 ml of methanol, and 222 mg (2.3 mmol) of sulfuric acid are added. The mixture is heated under reflux for 4 hours and then cooled to room temperature. The product which has precipitated out is filtered off with suction, washed with methanol and dried. 4.0 g (16.4 mmol; 75%) of N-carbomethoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][OH:14])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:7]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][O:14][S:53]([CH3:52])(=[O:55])=[O:54])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[N:7]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CCO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(CCOS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-hydroxypropoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (56 mg, 0.086 mmol) and TRIETHYLAMINE (0.036 ml, 0.259 mmol) in DCM (1.5 ml) at 0 C was added METHANESULFONYL CHLORIDE (0.013 ml, 0.173 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 C and quenched by addition of sat'd sodium bicarbonate. The reaction was diluted with ether and the layers separated. The ethereal was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 69 mg title compound (quantitative yield). LC/MS (HPLC method 1): tR=4.42 min, 726.2(MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][C:31]=2[CH:36]=O)=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][C:31]=2[CH:36]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.3 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (103 mg, 81%).