Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:15])[CH2:11][N:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]([O:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:11][N:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO[Si](C)(C)C(C)(C)C)CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.3 %

Procedure:
A toluene (10 mL) solution of crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol (1.0 g, 4.29 mmol, 1.0 equiv) was carefully added dropwise to a toluene suspension (5 mL) of NaH (60%, 0.17 g, 4.29 mmol, 1.0 equiv) at 0° C. under argon and the resultant was stirred for 15 minutes. A toluene solution (5 mL) of linoleyl methanesulfonate (1.47 g, 4.29 mmol, 1.0 equiv) was added dropwise to the stirring mixture and the reaction was then stirred for 18 hours at 90° C. The mixture was then cooled to room temperature and quenched by the slow addition of ethanol (10 mL). The mixture was then concentrated and the residue was taken up with deionized water (15 mL) and extracted three times with EtOAc (20 mL). The combined organic extracts were washed with deionized water (15 mL), dried (MgSO4), filtered, and concentrated. Chromatographic purification of the residue (0-5% MeOH in chloroform) yielded 109 mg (53% yield) of 3-(tert-butyldimethylsilyloxy)-N,N-dimethyl-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-amine, a thick clear oil.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:17][C:18]=2[CH:10]2[CH2:9][NH:8][CH2:26][CH2:25][CH:11]12
Reactant: BrCc1ccccn1
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1c2c(cc(OCc3ccccn3)cc2C(F)(F)F)C2CNCCC21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-Hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (1.0 eq.), bromomethylpyridine (2.0 eq.), and K2CO3 (4.0 eq.) were dissolved in anhydrous DMF(0.3 M). The mixture was stirred under Ar at rt for 24 h. Same work up and deprotection procedure were followed as described in Example 74 Method A and B to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][OH:16]
Reactant: O=Cc1cccn1NCc1ccncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccn1NCc1ccncc1F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cold solution of 1-(3-fluoro-4-pyridinylmethylamino)-1H-pyrrol-2-carboxaldehyde (5.0 g) in 100 ml of ethanol, was added NaBH4 (2.0 g). After stirring at 5° C. for one hour, and then at ambient temperature for an additional hour, the mixture was concentrated to an oil, which was stirred with 100 ml of water for five minutes and extracted with ethyl acetate. The organic layer was washed with water and dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[C:20]=1[NH2:26]>CCO.CC(O)=O>[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[N:25]=[C:21]3[CH:22]=[CH:23][CH:24]=[N:19][C:20]3=[N:26][C:8]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1cccnc1N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cccnc3nc2-c2ccc(C)cc2)cc1
Temperature: 85 °C

Procedure:
A solution of 1,2-dip-tolylethane-1,2-dione (commercially available)(175 g, 733 mmol) and pyridine-2,3-diamine (80 g, 733 mmol) in EtOH (1609 ml) and AcOH (179 ml) was heated to reflux (bath at 85° C.) for 1.5 h. The mixture was allowed to cool and concentrated in vacuo. The crude material was dissolved in DCM (500 ml) and filtered through silica to remove baseline impurities. The silica was washed with EtOAc (2 L). The combined filtrate layers were concentrated in vacuo to give a brown solid. The material was triturated in 1:1 TBME/heptane (300 ml). The solid was removed by filtration and washed with 1:1 TBME/heptane (200 ml) before drying at RT over 2 days to afford the title compound as an AcOH salt (1 eq).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:29]([CH3:28])[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CNCc1cccnc1
Product: CN(Cc1cccnc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with methyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[C:42](=[O:45])[CH2:43][CH2:44][CH:37]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([CH3:17])[C:18]2[CH:19]=[N:20][C:21]([N:41]3[CH2:40][CH2:39][N:38]4[C:42](=[O:45])[CH2:43][CH2:44][CH:37]4[CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC2CNCCN12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(N2CCN3C(=O)CCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 45.2 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 67 mg (0.483 mmol) of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 45 mg of the title compound as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
3,4-Dichlorobenzyl bromide (35.20 g, 150 mmol) was added to a solution of N-(tertbutoxycarbonyl)piperazine (24.84 g, 130 mmol) and triethylamine (20.91 ml, 150 mmol) in chloroform (100 ml) over 30 min. After 1 h, the reaction mixture was diluted with ethyl acetate and the product was precipitated out as the hydrochloride salt by adding 1N aqueous hydrogen chloride solution. The solid product was filtered, washed with water and then resuspended in ethyl acetate. Two equivalents of 1N aqueous sodium hydroxide solution was added and the free amine was extracted into ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to provide 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1>CCO.[Pd]>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[N:6]1[CH:7]=[C:3]([O:2][CH3:1])[N:4]=[CH:5]1)[NH2:14]
Reactant: COc1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1cn(-c2ccc(N)cc2OC)cn1
Reaction time: 2 h

Procedure:
4-Methoxy-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (0.62 g, 2.49 mmol) was dissolved in EtOH (20 mL). Palladium on carbon (10%, 0.106 g, 0.10 mmol) was added. The mixture was shaken for 2 hours under an atmosphere of hydrogen (g). The mixture was filtered, the filter was washed with warm EtOH. The filtrate was concentrated to give the title compound as an oil, 0.52 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[O:5].[C:37]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1)#[CH:38].C(N(CC)CC)C>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:37]#[C:38][C:33]2[CH:34]=[CH:35][C:2]([F:1])=[C:3]([CH:32]=2)[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[O:5])=[CH:40][N:41]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Reaction time: 16 h

Procedure:
In a 25-mL RBF (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.496 g, 0.80 mmol), 5-ethynylpyrimidin-2-amine (0.19 g, 1.6 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.040 mmol), and Copper(I) iodide (0.0076 g, 0.040 mmol) were taken up in CH3CN and Triethylamine (1.7 ml, 12 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70 deg. C. for 16 h. The reaction was cooled and transfered to a larger flask with EtOAc and concentrated in vacuo. The solid was adsorbed onto 4 g silica gel from 10% MeOH/MC purified by Isco {Redi-Sep® pre-packed silica gel column (80 g); eluent 0-75% EtOAc/hexanes over 30 min}. Product-containing fractions were concentrated to afford (S)-tert-butyl 1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate as a orange foam. MS m/z=613 [M+H]+. Calc'd for C31H32F4N6O3: 612.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=2)(=[O:30])=[O:31])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 10 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 7.55 g of 4-nitrobenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether mixture. m=14 g. M.p.=202° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH2:12][CH2:11]2.S(Cl)(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:39])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:39]2[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]2=[O:18])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Solvent: O=S(Cl)Cl
Product: COc1cc(N2CCc3cc(OC[C@@H]4CCCO4)ccc3C2=O)ccc1OCCN1CCCC1

Procedure:
6-[(S)-1-(Tetrahydrofuran-2-yl)methoxy]isochroman-1-one was firstly converted with thionyl chloride by method B into the corresponding dichloride, and then reacted with 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine by method A. The product with the molecular weight of 466.58 (C27H34N2O5) was obtained in this way; MS (ESI): 467 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:16]=1[CH2:17][N:18]([CH3:29])[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[CH2:21]([O:20][C:19]([N:18]([CH2:17][C:16]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH3:29])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
To sodium hydride (60% dispersion) (1.885 g, 47.1 mmol), was added DMSO (20 mL). The mixture was stirred for 5 min, then diethyl malonate (7.15 mL, 47.1 mmol) was added. The reaction mixture was stirred at rt for 15 min to give a clear colorless solution. To this mixture was added a solution of benzyl 2-fluoro-5-nitrobenzyl(methyl)carbamate (3 g, 9.43 mmol) in DMSO (1 mL) dropwise. The orange reaction mixture was stirred at rt for 1 h, then at 65° C. for 3 h. The reaction mixture was cooled to rt, quenched with sat. NH4Cl. The mixture was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 120 g column and eluted with a gradient from 0 to 30% ethyl acetate/hexanes) to give 10A (3.88 g, 8.46 mmol, 90% yield). MS (ESI) m/z: 458.9 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:16]#[C:17][Si](C)(C)C)[CH:15]=1)[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:16]([C:14]1[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C:9]2([CH3:24])[CH3:25])#[CH:17]
Reactant: CCOC(=O)c1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Yield: 83.2 %

Procedure:
A solution of ethyl-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman-6-carboxylate (Compound 25, 0.525 g, 1.47 mmol) in ethanol (5 mL) was treated with 2N aqueous sodium hydroxide solution (5 mL, 10 mmol) and the resulting solution was adjusted to pH˜5 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a brown solid (0.316 g, 84%).
Reaction SMILES: [H-].[Na+].[Na+].[I-].[C:5]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].Br[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=1[CH3:32])=[O:23].OP(O)(O)=O.[Br-].C([O-])(=O)CC([O-])=O>C1COCC1>[CH3:32][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C:5]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: Cc1cc(C)c(C(=O)CCCBr)c(C)c1
Agent: O=C([O-])CC(=O)[O-]
Agent: O=P(O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CCCC(=O)c1c(C)cc(C)cc1C)C(=O)OCC=C
Reaction time: 0.5 h

Procedure:
To a slurry of NaH (60% in mineral oil, 0.36 g) and NaI (0.55 g) in dry THF (37 mL) was added diallyl malonate (3.2 g, 18.5 mmol). The resulting slurry was stirred at room temp. for 30 min., then 4-bromo-1-(2,4,6-trimethylphenyl)-1-butanone (1.0 g, 3.7mmol) was added. This mixture was heated at the reflux temperature for 18 h, cooled to room temp., and acidified with a 1M H3PO4 solution (10 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL). The combined organic phases were sequentially washed with a 1M H3PO4 solution (100 mL), and a saturated NaCl solution (50 ml), dried (MgSO4), and concentrated under reduced pressure (kugelrohr, 80° C., (4 mmHg)) to give a crude oil which was further purified using rotary chromatography (SiO2, gradient from 1% EtOAc/hexane to 5% EtOAc/hexane) to give starting bromide (0.34 g) followed by the desired malonate (0.36 g). The resultant compound is illustrated below and was used in the next step without further purification as described in example 1 step 4. ##STR43##
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.C([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])C>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([N:50]([CH3:51])[CH2:49][C:48]([OH:47])=[O:52])=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Reactant: CCOC(=O)CNC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)N(C)CC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and sarcosine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 6.85-7.34 (m, 11 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.94 (m, 4 H), 2.98 (s, 3 H), 2.89 (s, 3 H), 2.80 (s, 1 H), 2.50 (m, 2 H), 2.33 (s, 3 H), 1.90 (m, 2 H); MS (ESI) m/z 682 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[C:9](=[O:10])[N:15]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[C:6]2=[O:8]
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
4-Methoxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-methoxyphthalic anhydride (1.0 g, 5.6 mmol) {Rao. A. V. R. et al, Indian J. Chem. 1981, 20 (B), 248}, 3-aminopiperidine-2,6-dione hydrogen chloride (0.92 g, 5.6 mmol) and sodium acetate (0.48 g, 6.0 mmol) in acetic acid (20 mL). The product was a white solid (0.44 g, 27% yield); mp, 281.5-282.5° C.; 1H NMR (DMSO-d6) δ2.00-2.08 (m, 1H, CHH), 2.56-2.62 (m, 2H, CH2), 2.82-2.91 (m, 1H, CHH), 3.97 (s, 3H, CH3), 5.08 (dd, J=5.3, 12.8 Hz, 1H, NCH), 7.46 (d, J=7.2 Hz, 1H, Ar), 7.52 (d, J=8.5 Hz, 1H, Ar), 7.84 (d, J=7.8 Hz, 1H, Ar), 11.10 (br s, 1H, NH); 13C NMR (DMSO-d6) δ21.97, 30.92, 48.73, 56.33, 115.24, 116.11, 119.01, 133.19, 137.15, 156.49, 165.37, 166.84, 169.94, 172.79; Anal Calcd for C14H12N2O5: C, 58.33; H, 4.20; N, 9.72. Found: C, 58.23; H, 3.90; N, 9.53.
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl.O>[CH3:15][C:4]1([CH3:16])[CH2:3][N:2]([N:1]2[CH2:25][CH2:26][CH2:27][C:28]2=[O:29])[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)CN(N)c2cc([N+](=O)[O-])ccc2O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CN(N2CCCC2=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 0.5 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.35 g of 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine and the solution was cooled on an ice bath. To this solution was added 0.16 g of triethylamine followed by dropwise addition of a solution of 0.18 ml of 4-chlorobutyryl chloride in 1.4 ml of methylene chloride. After 30 minutes, the reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was crystallized from ether to give 0.43 g of crude crystals of 4-chloro-N-(3,4-dihydro-2,2-dimethyl-6-nitro- 2H-1,4-benzoxazin-4-yl)butyrylamide. The crude crystals were used without purification in the next reaction. (4) In 8 ml of N,N-dimethylformamide was dissolved 0.41 g of the above amide and the solution was cooled on an ice bath. Then, 0.14 g of potassium tert-butoxide was gradually added. The mixture was stirred with ice-cooling for 1 hour, after which it was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and crystallized from ether. The crude crystals were recrystallized from ethanol to give 0.16 g of 3,4-dihydro-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][CH:5]1[O:10][C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6]1[OH:14])[CH3:3].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>Cl>[CH3:3][C:2]([CH3:15])([O:4][CH:5]1[O:10][C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6]1[O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC1OC(=O)CC(C)(C)C1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC1OC(=O)CC(C)(C)C1OS(C)(=O)=O
Reaction time: 2 h

Procedure:
A mixture of the product of Step A, 5 ml of pyridine and 1 ml of methanesulfonyl chloride was stirred for 31/2 hours and was then diluted with N hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 677 mg of residue was chromatographed over silica and was eluted with a 7-3 mixture of hexane-ethyl acetate to obtain 410 mg of 6-(1,1-dimethylethoxy)-5-methylsulfonyloxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 64° C.