Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([C:23](O)=O)[CH3:22])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>>[C:11]1([CH2:10][O:17][C:18](=[O:19])[N:20]([C@@H:21]([C:22]2[N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:9]=2)[CH3:23])[CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1cc(Br)cnc1N
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1

Procedure:
Synthesized according to the method of reagent preparation 19 by using 5-bromo-2,3-diaminopyridine and N-(benzyloxycarbonyl)-D-alanine in step 1 and 2-(trimethylsilyl)ethoxymethyl chloride in step 3. MS (EI) for C28H43BrN34O4Si2: 636 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br>>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[C:14]([S:15][CH3:16])[C:9]=1[C:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[N:1]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: BrCCOCCBr
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCOCC1

Procedure:
The title compound, white solid, MS: m/e=419.1 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1RS, 2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and bis(2-bromoethyl)ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[C:16]([F:22])[C:17]=2[F:21])=[O:8])[CH:10]=1
Reactant: CCOc1cccc(F)c1F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoyl chloride 21d (3.41 g, 13.4 mmol) and 1-ethoxy-2,3-difluoro-benzene 23b (2.42 g, 15.2 mmol) in dichloromethane (50 mL) was added anhydrous aluminium chloride (1.82 g, 13.7 mmol) in portions over 1 hours at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with hydrochloric acid (10 mL, 2 M) and extracted with dichloromethane (40 mL×4). The combined layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23d as yellow oil (5.03 g, 100%). This material was not further purified.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]([CH3:12])[CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCC1CCN(C)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CN(C)C(=O)c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
4-cyanobenzoylchloride (200 mg, 1.21 mmol) was dissolved in anhydrous CH2Cl2 (4 mL) and cooled to 0° C. Methyl-(1-methyl-piperidin-4-ylmethyl)-amine (172 mg, 1.21 mmol) in anhydrous CH2Cl2 (1 mL) was added followed by N,N-diisopropylethylamine (0.63 mL, 3.62 mmol). The reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain 4-cyano-N-methyl-N-(1-methyl-piperidin-4-ylmethyl)-benzamide as an off-white solid (213 mg, 65%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([OH:26])=O)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:34])([F:33])[CH2:30][CH2:31][NH2:32].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([NH:32][CH2:31][CH2:30][C:29]([F:34])([F:33])[F:28])=[O:26])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: NCCC(F)(F)F
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)NCCC(F)(F)F)nc2c1
Reaction time: 10 h
Yield: 17.6 %

Procedure:
A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (140 mg, 0.379 mmole), 3,3,3-trifluoropropan-1-amine (214 mg, 1.9 mmole), N-ethyldiisopropylamine (265 ul, 1.52 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 569 ul, 0.948 mmole) in tetrahydrofurane (7 ml) is stirred for 10 h at roomtemperature. The reaction mixture is poured on sat. aqueous sodium bicarbonate solution (60 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer is washed once with water, once with brine, dried with magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g silica cartridge (eluent dichloromethane+2% methanol) affords 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-N-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (31 mg, 17.6%) as a white foam. MS: m/z=465.3 (M+H+).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Br:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=2)=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2>CC#N>[Br:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[C:34]=2[F:21])=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
SelectFluor (20.5 g, 58 mmol, 2 equiv) was added portionwise to a solution of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (10 g, 29 mmol) in CH3CN (300 mL) at rt. The reaction mixture was stirred at rt for 0.5 h, quenched by addition of H2O and concentrated to remove CH3CN. The resulting mixture was diluted with EtOAc/H2O and filtered to provide a white solid (batch 1). The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford batch 2. The two batches were combined and purified by silica gel MPLC (Hex/EtOAc, 7:3) to afford a sample of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 94.3) and a sample of the title compound which was further purified by trituration in EtOAc to provide 2.28 g of a white solid. Title compound: ESI-MS: 381.0/382.9 [M+H]+; tR=4.92 min (System 1); TLC: Rf=0.26 (Hex/EtOAc, 7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCOCC3)ccc21
Yield: 103.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with morpholine (0.100 mL, 1.15 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (154 mg, 0.727 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(morpholinomethyl)indol-2-yl]isoindolinone (36.5 mg).
Reaction SMILES: [OH2:1].[CH2:2]([N:4]([CH2:26][CH3:27])[CH2:5][CH2:6][NH:7][C:8]([C:10]1NC(C2C=CC=CC=2)=[C:13]2[C:18]=1[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14]2)=[O:9])[CH3:3].[C:28]([OH:31])(=O)[CH3:29]>>[ClH:19].[CH2:26]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][NH:7][C:8](=[O:9])[C:10]([C:18]1[CH:17]=[CH:16][C:15]([C:28](=[O:31])[C:29]2[CH:10]=[CH:18][CH:13]=[CH:14][CH:15]=2)([Cl:19])[CH2:14][CH:13]=1)=[O:1])[CH3:27]
Reactant: O
Reactant: CCN(CC)CCNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CC(=O)O
Product: CCN(CC)CCNC(=O)C(=O)C1=CCC(Cl)(C(=O)c2ccccc2)C=C1
Product: Cl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
86.4 G. of ceric ammonium nitrate are dissolved in 150 ml. of water and 150 ml. of glacial acetic acid. 22.2 G. of 5-chloro-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide are added and the mixture is stirred at 80° C. for 20 minutes, the color of the solution obtained changing from orange to light yellow. After cooling, 750 ml. of ice-water are added and the separated oil is extracted with methylene chloride. The extract is washed with 2-N ammonium hydroxide and a saturated sodium chloride solution, dried over sodium sulfate and evaporated. The oily residue is dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The precipitated hydrochloride is removed by filtration, washed with diethyl ether and dried over phosphorus pentoxide in a desiccator. After recrystallization from methylene chloride/diethyl ether, there is obtained p-benzoyl-p-chlorophenylglyoxylic acid [2(diethylamino)ethyl]amide hydrochloride in the form of almost colorless crystals having a melting point of 161°-164° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:31]([O:30][C:29](=[O:38])[NH:28][CH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:22]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)phenol (1.5 g, 5.54 mmol) was suspended in anhydrous CH2Cl2 (15 mL) and cooled to 0° C. under an N2 atmosphere. A mixture of benzyl (piperidin-3-yl)methylcarbamate hydrochloride (1.73 g, 6.09 mmol) in CH2Cl2 (20 mL), and triethylamine (23 mL, 16.67 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and the reaction was complete after one hour. It was then partitioned between CH2Cl2/H2O, and separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to an orange solid. Purification by silica gel chromatography using 98% CH2Cl2/2% EtOAc gave benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as a bright yellow solid (1.75 g, 66%). LC/MS: m/z 483.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[S:14][C:13]2[CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:9]=2[CH:8]=1.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[S:14][C:13]2[C:12]([CH:23]=[O:24])=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2sc(Br)cc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Br)sc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To DMF (2.05 mL) cooled by ice/water was added POCl3 dropwise and the mixture was stirred for 30 min. A solution of carboxylate 61 (1.96 g, 7.15 mmol) in DMF (2.5 mL) was added at this temperature and the mixture was allowed to warm to room temperature then heated to 60° C. After 16 h, the reaction mixture was cooled to room temperature, and poured into ice/water. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4. After removed the organic solvent, the residue was purified by column chromatography (EtOAc/Hexane: 1/4) to give the desired aldehyde 62 (1.62 g, 75%) as a white solid.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:33]1[CH:34]=[C:35]([C:41]#[N:42])[C:36](=[CH:39][CH:40]=1)[C:37]#[N:38])([O-])=O>O.C1(C)C=CC=CC=1>[C:41](#[N:42])[C:35]1[C:36](=[CH:39][CH:40]=[CH:33][CH:34]=1)[C:37]#[N:38]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 310.1 %

Procedure:
To a 100 ml, 3-necked flask equipped with a thermometer and a Dean-Stark trap was added 5.0 gm (22.9 mmol) of 4,4'-difluorobenzophenone, 11.56 gm (34.4 mmol) of bisphenol A6F, and 80 ml of N-methyl pyrrolidinone (NMP). After flushing the mixture for 30 minutes with dry nitrogen, 7.6 gm (55.1 mmol) of pulverized anhydrous potassium carbonate was added with stirring. The reaction mixture was stirred at 100° C. for 1 hour. Toluene was added to the Dean-Stark trap and to the reaction vessel (4 ml). The reaction mixture was refluxed at 175°-180° C. for 12 hours. Water which formed as a by-product was removed by azeotropic distillation. The reaction temperature was reduced to 160° C. and the toluene was sweep out of the reaction vessel by removing the glass stopper from the 3-necked flash. When the temperature reached 180° C., it was assumed that the toluene had been removed. Upon cooling to room temperature, 3.97 gm (22.9 mmol) of 4-nitrophthalonitrile was added. The temperature of the mixture was increased to 100° C. and held at this temperature for 4 hours. FTIR spectroscopy showed the absence of hydroxy and nitro bands. The room temperature mixture was then poured into 400 ml of water with stirring. The solid precipitate was collected by suction filtration, washed exhaustively with water, and dried to afford 9.1 gm of oligomeric phthalonitrile monomer.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].[OH:20]O>C(O)(=O)C.O[W](O)(=O)=O>[C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])(=[O:20])=[O:16])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2]
Reactant: OO
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(S(C)=O)cc1
Agent: O=[W](=O)(O)O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
The above 4-(methylsulfonyl)phenyl compound also was prepared from the corresponding 4-(methylsulfinyl)phenyl compound as follows: to a stirred warm solution containing 0.8 g of 3-cyano-6-methyl-5-[4-(methylsulfinyl)phenyl]-2(1H)-pyridinone in 30 ml of glacial acetic acid was added 500 ml tungstic acid and to the resulting stirred solution was added dropwise over a period of 2 minutes a solution containing 0.102 g of hydrogen peroxide in acetic acid (32.97 mg/ml/3.1 ml) and the resulting reaction mixture was stirred at room temperature for 1 hour and then heated occasionally over a period of 1 hour. After tlc analysis indicated a small quantity of methylsulfinyl compound still present, and additional 3 ml of said hydrogen peroxide solution was added and heating as above was continued for 1 hour. The hot reaction mixture was filtered thru diatomaceous earth to remove the tungstic acid, the filter pad washed with warm acetic acid and the filtrate stripped, first in vacuo and then under high vacuum. The remaining solid residue was slurried in about 75 ml of hot absolute ethanol and the mixture cooled slightly. The solid was collected, washed with ethanol and dried at 65° C. in vacuo to yield 0.7 g of 3-cyano-6-methyl-5-[4-(methylsulfonyl)phenyl]-2(1H)-pyridinone, m.p. 311°-313° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[O:7][CH2:6]1)[CH3:3].[O:16]([C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26](OC(=O)[C:24]=12)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:34](N(C(C)C)CCOC1C=CC(N)=CC=1OC)(C)C>>[CH3:3][N:2]([CH3:1])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N:15]3[CH2:26][C:25]4[C:31](=[CH:32][CH:33]=[C:23]([O:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:24]=4)[CH2:34]3)=[CH:11][CH:12]=2)[O:7][CH2:6]1
Reactant: CN(C)CC1COc2cc(N)ccc2C1
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Reactant: O=C1OC(=O)c2c(Oc3ccccc3)cccc21
Product: CN(C)CC1COc2cc(N3Cc4ccc(Oc5ccccc5)cc4C3)ccc2C1

Procedure:
3-Dimethylaminomethyl-chroman-7-ylamine[WO 0121577 A2] was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>ClCCl>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1N
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of benzene-1,2-diamine (100 g, 0.93 mol) in dichloromethane (1 L) at 0° C. was added acetic anhydride (87 mL, 0.92 mol). After stirring at 0° C. for 2 hours, the mixture was stand at 0° C. for 12 hours and the precipitate was collected by filtration, washed by dichloromethane and ether, dried in air to afford the product N-(2-aminophenyl)acetamide (25 g, yield 18%). 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.26 (m, 2H), 7.04-7.08 (m, 1H), 6.78-6.81 (m, 2H), 3.86 (br s, 2H), 2.20 (s, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(Cl)Cl.C(OCC)(=O)C>[CH:26]1([NH:29][C:2]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)ccc1NC1CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
1 g of 2-fluoro-5-trifluoromethyl-benzoic acid (4.81 mmol) was dissolved in DCM (10 ml) and 1.03 ml of oxalylchloride (12.01 mmol) and a drop of DMF were added at RT. The mixture was stirred for 1 h before all volatile materials were removed in vacuo. The remaining residue was again dissolved in DCM (10 ml) and 1.4 ml of ethanol was added. After 1 h the reaction mixture was diluted with DCM and then washed with 10% aqueous KHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated. The remaining material was dissolved in DMSO (6 ml), 5.57 ml of cyclopropylamine (79.4 mmol) were added and the mixture was heated to 110° C. over night in a sealed tube. The reaction mixture was then cooled to RT, diluted with ethyl acetate, washed with diluted HCl, 10% aqueous KHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated. Then THF (20 ml), methanol (10 ml) and 8 ml of a 1N LiOH solution were added and the resulting solution was stirred over night at RT. The organic solvents were then removed in vacuo and the solution was acidified with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The remaining solid was triturated with a small amount of chloroform. Filtration gave 391 mg (33%) of the title compound as light brown crystals. 1HNMR (DMSO-d6, 300 MHz): δ 0.53 (m, 2H), 0.85 (m, 2H), 2.56 (m, 1H), 7.24 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.9 and 2.1 Hz, 1H), 8.02 (s, 1H), 8.30 (br s, 1H), 13.21 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[C:4](=[O:19])[N:3]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][CH:2]1[CH2:6][C:5]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:4](=[O:19])[N:3]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1
Reactant: CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl 3-methyl-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (90 mg, 0.257 mmol) was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated to remove excess of the reagent and co-evaporated with dichloromethane three times to give the title compound. LC-MS (IE, m/z): 251 (M+1)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][CH2:10][CH2:11][C:12]([NH:14][NH2:15])=[O:13].[OH:16][C:17]1[C:34]2[CH2:33][C@@:32]([OH:39])([C:35](=O)[CH2:36][OH:37])[CH2:31][C@H:30]([O:40][C@@H:41]3[O:55][C@@H:54]([CH3:56])[C@H:44]4[O:45][C@H:46]5[N:51]([C@H:43]4[CH2:42]3)[CH2:50][CH2:49][O:48][C@@H:47]5[O:52][CH3:53])[C:29]=2[C:28]([OH:57])=[C:27]2[C:18]=1[C:19](=[O:61])[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:59][CH3:60])[C:25]=1[C:26]2=[O:58]>CO>[OH:37][CH2:36]/[C:35](=[N:15]\[NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)/[C@@:32]1([OH:39])[CH2:31][C@H:30]([O:40][C@@H:41]2[O:55][C@@H:54]([CH3:56])[C@H:44]3[O:45][C@H:46]4[N:51]([C@H:43]3[CH2:42]2)[CH2:50][CH2:49][O:48][C@@H:47]4[O:52][CH3:53])[C:29]2[C:34](=[C:17]([OH:16])[C:18]3[C:19](=[O:61])[C:20]4[C:25]([C:26](=[O:58])[C:27]=3[C:28]=2[OH:57])=[C:24]([O:59][CH3:60])[CH:23]=[CH:22][CH:21]=4)[CH2:33]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: NNC(=O)CCSSc1ccccn1
Agent: Cl
Solvent: CO
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(/C(CO)=N/NC(=O)CCSSc1ccccn1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.1 %

Procedure:
A solution of 3-(2-pyridyldithio)propionic acid hydrazide HCl (41.5 mg, 0.156 mmol) in anhydrous methanol (5 ml) was added to (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [PNU-159682, compound IIA, prepared as reported in WO 9802446] (50 mg, 0.078 mmol). The solution was stirred in the dark at room temperature for 20 hours. The course of the reaction was followed by reverse-phase HPLC-MS. After this period the solvent was evaporated and the residue was purified by flash column chromatography (MeOH:CH2Cl2=0.2:9.8) on silica gel (230-400 mesh), affording 18 mg (yield 27%) of 53. MS (ESI): 853 [M+H]+. Retention time=5.52 min (method 2).