Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:19][CH:20]=1)(=[O:12])=[O:11]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)c(C)c1
Reaction time: 0.08 h

Procedure:
A solution of 6.6 g (0.03 mol) of 2,4,6-trimethylbenzenesulfonyl chloride in 50 ml chloroform is added at room temperature to a stirred slurry of 6.3 g (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 100 ml chloroform, the slurry additionally containing 4 ml (0.03 mol) triethylamine, portionwise over a five minute period. After 3 hours stirring the reaction mixture is filtered. The chloroform solution is thereafter washed with water, dilute hydrochloric acid, and water, in that order, separated from the water layer, dried over anhydrous magnesium sulfate and evaporated. The recovered 3-[4-(2,4,6-trimethylbenzenesulfonamido)benzenesulfonyl]acrylonitrile has the formula: ##SPC18##
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[Li+].[CH3:16][CH:17]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:16]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1)[CH3:17]
Reactant: COC(=O)CC1=CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1C=C(CC(=O)OC)c2ccccc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl inden-3-ylacetate from Example 13, Step 1 (1 g, 5.32 mmol) in THF (10 mL) at −70° C. was added dropwise a solution of LDA (12.2 mL, 0.87 M, 2 eq.) in THF. The resulting orange solution was stirred for 30 minutes at −70° C. and then ethyl iodide (0.47 mL, 5.85 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was left to warm to room temperature while a precipitate appeared. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 1N HCl, then with brine, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel, eluting with a 1:19 mixture of ethyl acetate-hexane to afford pure title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.FC1C(F)=C(F)C(F)=C([O:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]2[C@@H:37]3[C@@H:32]([NH:33][C:34]([NH:36]3)=[O:35])[CH2:31][S:30]2)=O)C=1>CN(C=O)C>[C:23]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1
Reactant: CC(N)CC(=O)O
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2cc(F)c(F)c(F)c2F)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Preparation was accomplished as described by Wilbur [Bioconj. Chem. 1997, 8, 572]. To a 0.13 g (1.3 mmol) quantity of 3-aminobutyric acid dissolved in 20 mL of DMF under argon atmosphere was added 0.4 mL (2.5 mmol) of triethylamine followed by 0.5 g (1.3 mmol) of biotin tetrafluorophenyl ester. The reaction was stirred at 25° C. for 24 h and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under vacuum to yield 0.5 g (98%) of product as a colorless solid, mp 161-163° C. 1H NMR (DMSO-d6): O 7.6 (m, 1H), 6.2 (d, J=11.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.6 (m, 2H), 2.35 (d, J=12.6 Hz, 1H), 1.7-2.1 (m, 4H), 0.7-1.5 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[CH2:5][C:6]#[CH:7].O>O1CCCC1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([CH:5]=[C:6]=[CH2:7])[C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9]
Reactant: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Solvent: C1CCOC1
Solvent: O
Product: C=C=CN(C(=O)c1ccco1)c1c(C)cccc1C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
50 g (0.2 mol) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline were dissolved in 200 ml of anhydrous tetrahydrofuran, and 150 mg of potassium tert.-butylate were added. During this procedure, the temperature of the solution rose to about 50° C., the solution becoming colored. The reaction mixture was left to stand for 2 hours and then poured onto 500 ml of water. The crystalline product which had precipitated was filtered off, dried and recrystallized from ethyl acetate/petroleum ether. 24 g (48% of theory) of 2,6-dimethyl-N-allenyl-N-(2-furoyl)-aniline of melting point 138°-41° C. were obtained. (The 1H-NMR spectrum indicated complete isomerization). ##STR99##
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.Br[C:17]1C=CC(C(O)=O)=C(Cl)[CH:18]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:15][C:4]1[CH:3]=[C:2]([CH:17]=[CH2:18])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
tert-Butyl 4-bromo-2-chlorobenzoate (AI18). To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR (thin film) 1728 cm−1.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](O)[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:21])[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(O)nc(SCc2ccccc2)n1
Product: CCCc1cc(Cl)nc(SCc2ccccc2)n1
Temperature: 20 °C

Procedure:
A mixture of 72 g (0.28 mole) of 2-benzylthio-4-hydroxy-6-n-propylpyrimidine (from Part A) and 100 ml of phosphorus oxychloride was heated at reflux for three hours, and was then allowed to cool to 20° C. After evaporating in vacuo the residue was poured into ice water with vigorous stirring. The mixture was extracted with three 75 ml portions of diethyl ether, and the extracts were dried over magnesium sulfate and evaporated to provide a yellow oil residue of 2-benzylthio-4-chloro-6-n-propylpyrimidine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][NH:13][CH3:14].C(O)C>>[CH3:12][N:13]([CH3:14])[C:3](=[O:2])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: CNC
Solvent: CCO
Product: CCCCC(=O)CC(=O)N(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
0.632 mol (100 ml) methyl-3-oxoheptanoate (3-oxo-heptanoic acid methylester) and 227 ml 33% dimethylamine solution in ethanol (approx. 1.26 mol dimethylamine) was stirred for 4 hours at 110° C. in a pressure reactor. After cooling off, the solvents were distilled off on a rotavap, the raw product was taken up in 40 ml water, 30 ml 32% HCl and 40 ml ethanol and stirred for 24 hours at 100° C. The mixture was again concentrated to dryness by evaporation, taken up again in 300 ml acetic ester and filtrated, the solvents were then distilled off on the rotavap. 26 g of raw product was purified over 500 g silica gel 60 (mobile solvent: acetic ester:hexane 1:1, flow 50 ml/min, fraction size: 100 ml, product: fractions 20-35), the product was obtained as a mobile oil. 17.8 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][C:23]=1[C:29](=[O:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16](/[CH:17]=[CH:18]/[C:27]3[C:22]([OH:21])=[C:23]([C:29](=[O:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCCCCc2ccc(F)cc2)cc1
Reactant: CC(=O)c1cccc(I)c1O
Product: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccc(F)cc3)cc2)c1O
Yield: 70 %

Procedure:
Following the process described in example 20 (point D), starting from 4-[4-(4-fluorophenyl)butoxy]-styrene and 2'-hydroxy-3'-iodoacetophenone, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 95:5 (70% yield).
Reaction SMILES: [NH2:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[C:14]([O:18][C:19]([NH:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1(CCC(=O)O)CC=CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(CCC(=O)O)CC=CO1

Procedure:
5.0 pts. by wt. of 2-amino-furfurylacetic acid (Rohm and Haas, Netherlands Application No. 66,07754) in 100 pts. by vol. of 80 percent strength aqueous dioxane are brought to pH with 4 N sodium hydroxide solution. 8.0 pts. by wt. of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile are added and the mixture is warmed to 70° for 2 hrs. During this time, the above pH is maintained by adding 4 N sodium hydroxide solution. Thereafter, 80 pts. by vol. of water are added, the dioxane is stripped off and the reaction mixture is extracted several times with ethyl acetate. The aqueous phase is brought to pH 4 with 10 percent strength citric acid, and is saturated with sodium chloride and extracted by shaking with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and concentrated. The residue is recrystallized from a little abs. carbon tetrachloride. 4.3 pts. by wt. of 2-t-butoxycarbonylamino-furfurylacetic acid of melting point 99°-101° are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].[N+]([O-])(O)=O.C(O)(=O)C>C(O)(=O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2[N+](=O)[O-])N1
Reaction time: 19 h
Yield: 41 %

Procedure:
A suspension of the product of Example 352C (100 mg, 0.352 mmol) in glacial acetic acid (3 mL) was treated at room temperature with a solution of concentrated nitric acid in glacial acetic acid (1.43 M, 0.305 mL, 0.436 mmol) and stirred at this temperature for 19 hours. Added additional 1.43 M nitric acid/acetic acid (0.020 mL, 0.029 mmol) and let stir for 1.5 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 8% methanol/dichloromethane to give the title compound as a light yellow solid (47 mg, 41%). MS (ESI−) m/z 328 (M−H)−. 1H NMR (300 MHz, PYRIDINE-d5) δ 0.98 (t, J=7.17 Hz, 3 H) 3.86 (s, 2 H) 4.01 (q, J=7.23 Hz, 2 H) 7.11 (d, J=8.82 Hz, 1 H) 7.22 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(3-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 18 & 19, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7].C1(C)C=CC=C(OC2C=CC=CC=2OC(=O)[CH:38]=[N:39]OC)C=1.CN>>[CH3:38][NH:39][C:3](=[O:2])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7]
Reactant: CON=CC(=O)Oc1ccccc1Oc1cccc(C)c1
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1cccc(C)c1
Agent: CN
Product: CNC(=O)/C(=N\OC)c1ccccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To Product (A') (286 mg), i.e. methyl-(Z)-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, [2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, 30 % methanolic methylamine (197 mg) was added, followed by stirring at room temperature for 12 hours. Excess amine and methanol were removed from the mixture, which was subjected to silica gel column chromatography with a mixture of hexane and ethyl acetate to give 201 mg of (Z)-N-methyl-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetamide (Compound No. 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:18][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[N:28][C:20]=3[CH3:19])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1N
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-ethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in 40% yield. 1H-NMR (300 MHz, MeOH-d4): δ 1.39 (t, 3H), 2.76 (s, 3H), 4.14 (q, 2H), 7.43 (dd, 1H), 8.05 (d, 1H), 8.26 (m, 3H), 8.55 (d, 1H), 8.79 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].F[C:25]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:13]3[C:22](=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)[O:23][CH2:25]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%): 1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 2H), 6.87-6.79 (m, 1H), 6.43 (s, 1H), 6.16 (s, 1H), 4.93 (ABq, 2H), 4.22-4.07 (m, 4H), 3.24 (s, 3H); MS (ES+) m/z 387.9 (M+1), 389.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][CH:4]=1.II.[I:24](O)(=O)(=O)=O>C(O)C.O>[I:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][CH:9]([C:13]([F:14])([F:15])[F:16])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2ccc(OC)cc2OC1C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Temperature: 70 °C
Yield: 86.4 %

Procedure:
To a solution of 8 g (26.5 mmol) of ethyl 7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 60 mL of ethanol was added 2.8 g (11.2 mmol) of iodine, followed by addition of a solution of 9.0 g (39.5 mmol) of periodic acid in 25 mL of water. The resulting solution was heated to 70° C. for five hrs. After cooling to room temperature, the volatiles were removed, the residue was dissolved in ethyl acetate, and the organic phase washed with saturated aqueous sodium sulfite and satr' brine. The resultant solution was dried over anhydrous magnesium sulfate and the volatiles were removed. The residue was purified by silica gel chromatography with hexane/ethyl acetate mixture to afford 9.8 g (70%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.62(s, 1H), 7.60(s, 1H), 6.49(s, 1H), 5.69(q, J=6.9 Hz, 1H), 4.30(m, 2H), 3.89(s, 3H), 1.34(t, J=7.2 Hz, 3H). MS (ESI+) 428.9(M+1, 100). HRMS (EI) m/z calcd for (C14H12F3O4) 427.9732, found 427.9741.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)nn(CCN3CCCC3)c2c1
Temperature: 50 °C
Yield: 65 %

Procedure:
A mixture of 3-chloro-6-nitro-1H-indazole (2.4 g, 12 mmol) was treated with potassium carbonate (5.0 g, 36 mmol) in DMF (40 mL) for about 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine (3.1 g, 18 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (2.3 g, 66%). 1H NMR (300 MHz, DMSO-d6) ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.89 (t, J=6.44, 2H), 4.67 (t, J=6.44, 2H), 7.90 (m, 1H), 8.01 (m, 1H), 8.86 (m, 1H); MS (DCI/NH3) m/z 295 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.Cl>[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCCCn1c(C)cc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part A of Example 2, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.07 mole) of 76 percent active 1-n-butyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted in 100 ml of benzene. The reaction mixture was drowned in 200 ml of five percent hydrochloric acid with stirring. The solid which formed was collected by filtration, washed with water and dried to obtain 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)3CH3), a pale yellow solid melting at 162°-164° C. The nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][NH:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][N:10]2[S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a stirring suspension of sodium hydride (0.677 g, 16.92 mmol) in THF (25 ml) at 0° C. was added a solution of 6-bromo-3-fluoro-4-nitro-1H-indazole (4 g, 15.38 mmol) in THF (25 ml) dropwise. The reaction mixture was allowed to stir for 30 min then allowed to warm to room temperature before benzenesulfonyl chloride (2.170 ml, 16.92 mmol) was added. after approximately 2 h the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous was then extracted again with ethyl acetate. The combined organics were then washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with 50 ml methanol and filtered to yield the title compound as a yellow solid (5.96 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[CH2:31]([NH2:34])[CH2:32][NH2:33]>C1COCC1>[NH2:33][CH2:32][CH2:31][NH:34][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:10]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:11]=2[N:12]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Reactant: NCCN
Solvent: C1CCOC1
Product: NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Yield: 97.2 %

Procedure:
To a solution of 4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (30 mg, 0.070 mmol) in dry THF (1 mL) was added ethylenediamine (23 uL, 0.35 mmol). The white precipitate initially formed redissolved on stirring. The mixture was stirred for about 15 min at about 20° C. LC/MS showed no starting material. The solvent was evaporated and the residue redissolved in DCM (1 mL) and water (1 mL). The layers were separated and the aqueous phase was basified with 2M sodium hydroxide (1 mL). The aqueous phase was extracted with DCM (2×1 mL) and the combined organic layers were evaporated to give 28 mg (100%) of the title compound. LC-MS m/z 412 (M+H)+, 2.19 min (ret time).