Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:15]=[C:14]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=4)[C:29]#[N:30])[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>COCCOC>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]3[CH:13]=[C:14]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([C:29]5[NH:38][N:37]=[N:36][N:30]=5)[CH:31]=4)[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1cncc(-c2cc(NCc3cccc4[nH]ccc34)nc(-c3ccccn3)n2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: c1ccc(-c2nc(NCc3cccc4[nH]ccc34)cc(-c3cncc(-c4nnn[nH]4)c3)n2)nc1
Temperature: 25 °C

Procedure:
A solution of 5-(6-[(1H-indol-4-ylmethyl)-amino]-2-pyridin-2-yl-pyrimidin-4-yl)-nicotinonitrile (Ex. 2.9) (50 mg, 0.124 mmol) in DME (2 ml) under an inert atmosphere of argon is treated with trimethylsilyl azide (5 eq, 70 mg, 0.248) and dibutyltin oxide (0.3 eq, 9.3 mg). The resulting mixture is heated at reflux for 4 hours and then allowed to cool to room temperature. On cooling, a solid precipitates which is collected by filtration, washed with MeOH and dried in vacuo at 40° C. overnight to afford the title compound [M+H]+=447.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.[CH3:31][N:32]1[C:36](=O)[CH2:35][CH2:34][CH2:33]1>>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:32]2[CH2:31][CH2:36][CH:35]=[CH:34][CH2:33]2)[N:7]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Reactant: CN1CCCC1=O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(N3CC=CCC3)n1)nn2C1CCCCO1
Yield: 83 %

Procedure:
A slurry of 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.500 g, 1.171 mmol) and 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.461 g, 0.974 mmol, 83% yield) in 2 mL NMP was sealed and heated to 120° C. The reaction became an orange/brown solution. After 1 h, the reaction was complete. The reaction was partitioned between water and EtOAc. The organic layer was washed with water once, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-40% EtOAc/hexane. The desired fractions were concentrated to afford 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.461 g, 0.974 mmol, 83% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25](=[O:26])[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17]2)=[CH:12][CH:11]=1.[CH3:27][SiH:28]([CH3:30])[CH3:29]>C1COCC1.CCOC(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][C:18]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:23][CH:24]=[C:25]2[O:26][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:12][CH:11]=1
Reactant: C[SiH](C)C
Reactant: O=C1CCC2(CC1c1ccc(F)cc1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCC2(CC1c1ccc(F)cc1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Step AAC (1): Followed a method described by A. de Meijer et. al Chem. Eur. J. 2007, 13, 3739. Lithium diisopropylamide (1.8 M in THF, 1.26 mL, 2.26 mmol) was added to a −78° C. solution of 7-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-one (515 mg, 2.06 mmol, O. Dirat et. al Tetrahedron Lett. 2006, 47, 1295) in THF (7 mL). The resulting mixture was allowed to stir for 1 hr. Trimethylsilane (0.289 mL, 2.264 mmol) was added and the mixture was allowed to warm to rt and stir for 30 min. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo to afford (9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-8-yloxy)trimethylsilane (696 mg, 100% yield) as a yellow solid. The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10](=[O:15])[NH:11][CH2:12][CH2:13][OH:14])[CH3:9])(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@H:8]([CH3:9])[C:10]([NH:11][CH2:12][CH2:13][OH:14])=[O:15]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.78 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1.8 ml, 23.4 mmol) was slowly added. The pale yellow reaction mixture was stirred at room temperature for 2 h then concentrated to afford (R)-2-amino-N-(2-hydroxy-ethyl)-propionamide trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:28][CH3:29])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.2 g (20 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman were introduced in portions at 10° C. into a suspension of 0.82 g (27 mmol) of sodium hydride (80 per cent dispersion) in 60 ml of DMA. After stirring at RT for 2 h, 2.2 ml (26.5 mmol) of ethyl iodide were added dropwise, the temperature rising to 32° C. The mixture was then heated to 35-40° C. for 2 h, concentrated in vac., treated with water, the resinous product was taken up EA, the solution was dried and concentrated and the residue was chromatographed using n-heptane/EA (2:1) on silica gel. 6 g of product were crystallized from appropriate fractions using petroleum ether/diisopropyl ether (1:1), m.p. 104-106° C.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]2[C:11](=[O:25])[N:12]([CH3:24])[CH2:13][C:14]3[N:15]([CH:16]=[N:17][C:18]=3[C:19]([O:21]CC)=O)[C:9]=2[CH:8]=[CH:7][C:6]=1[F:26]>C(O)C>[Cl:4][C:5]1[C:10]2[C:11](=[O:25])[N:12]([CH3:24])[CH2:13][C:14]3[N:15]([CH:16]=[N:17][C:18]=3[C:19]([NH:2][NH2:3])=[O:21])[C:9]=2[CH:8]=[CH:7][C:6]=1[F:26]
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)c(Cl)c2C1=O
Yield: 63 %

Procedure:
9.15 ml of hydrazine hydrate were added to a suspension of 5.47 g (0.00162 mol) of ethyl 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 55 ml of ethanol and the mixture was heated at reflux for 18 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 3.28 g (63%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide as white crystals; m.p. 308°-310°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Reactant: N#Cc1ccc2c(c1)CC[C@@H](N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN([C@@H]3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from (6R)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH:22]1[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=S1CCNCC1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCS(=O)CC1
Yield: 37 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and thiomorpholine 1-oxide and purified by flash chromatography (ethyl acetate), yield 37%. White crystals, m.p. 156-157° C.; 1H NMR (CDCl3)δ 8.47-8.40 (s-like, 1H), 7.94-7.87 (dd-like, 1H), 7.24-7.13 (m, 4H), 7.06-6.99 (d-like), 4.31-3.91 (m, 4H), 2.97-2.87-2.75 (m, 2H+2H); IR (KBr): ν 1710 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([OH:19])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH:6]=[CH:5]2.[CH3:20]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([O:19][CH3:20])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(C(O)Cn3ccnc3)ccc2c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(Cn1ccnc1)c1ccc2cc(C)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.38 g. of 1-[2-(6-methyl-2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. of hexamethylphosphoramide under nitrogen is added 480 mg. of a 56% dispersion of sodium hydride in mineral oil. After stirring for 1 hour at room temperature, the temperature is adjusted to 50° C. and stirring is continued for 1 to 2 hours. The reaction mixture is then cooled to about 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter, the solution is stirred at 5° to 10° C. for 1 hour, at room temperature for 4 hours and then heated at 50° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue may be chromatographed on silica gel to effect purification of the free base. Elution of the gel with 5 to 10% methanol in dichloromethane yields 1-[2-(6-methyl-2-naphthyl)-2-(methoxy)ethyl]imidazole.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6](=O)[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)C.[C:21]([C:24]1[C:25]([C:31]([F:34])([F:33])[F:32])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=1)(=[NH:23])[NH2:22]>>[CH3:19][O:18][C:9]1[CH:8]=[C:7]([C:6]2[N:5]=[CH:4][N:22]=[C:21]([C:24]3[C:25]([C:31]([F:32])([F:34])[F:33])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=3)[N:23]=2)[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[O:16][CH3:17]
Reactant: N=C(N)c1ccc[n+]([O-])c1C(F)(F)F
Reactant: COc1cc(C(=O)/N=C/N(C)C)cc([N+](=O)[O-])c1OC
Product: COc1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of (E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol) ethanol (30 mL) was added 3-carbamimidoyl-2-(trifluoromethyl)pyridine 1-oxide (0.82 g, 4 mmol). The reaction mixture was heated to reflux for 5 hours. It was cooled to room temperature and the solvent was removed by evaporation. The residue was then dissolved in dichloromethane/isopropanol mixture (50 mL, 70:30) and the organic phase was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from ethanol to give 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.27 g (75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([CH2:7]Br)=[CH2:6])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH2:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(CBr)C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(CN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a solution of 2-bromomethyl-acrylic acid ethyl ester (1.93 g, 10 mmol) in N,N-dimethylformamide (25 mL) was added piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 10 mmol) and then, dropwise, ethyl-diisopropyl-amine (1.71 mL, 10 mmol). After stirring for 16 h at room temperature the solvent was removed under reduced pressure and water (50 mL) and dichloromethane (50 mL) were added. After stirring for 2 min the layers were separated, the organic was washed with water and brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure to give crude 4-(2-ethoxycarbonyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester (2.456 g, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.ClCCl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:19])=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
A mixture of 2-benzyloxyphenylacetic acid (242 mg, 11.0 mmol), N-bromosuccinimide (178 mg, 1.9 mmol) and dichloromethane (4 ml) was stirred overnight at room temperature under argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (280 mg, 87.2%) as a white solid.
Reaction SMILES: CO[CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13].C([O:18][N:19]=O)CCC.[O-]CC.[K+]>>[OH:18][N:19]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13]
Reactant: COC1CCc2ccccc2C1=O
Reactant: CCCCON=O
Agent: CC[O-]
Agent: [K+]
Product: O=C1C(=NO)CCc2ccccc21

Procedure:
Most of the 5, 6, 7, and/or 8-methoxy-1-tetralones are known. See, e.g., Autrey & Scullard, J. Am. Chem. Soc. 90, 4924 (1968); Thomas and Nathan, J. Am. Chem. Soc. 70, 331 (1948); Thrift, J. Chem. Soc. C., 288 (1967). The appropriate methoxy 1-tetralone (Compound 1) is reacted with n-butylnitrite and potassium ethoxide to yield the 2-hydroxyimino-1-tetralone (Compound 2). The latter is reduced over palladium-barium sulfate to give the 2-amino-1-tetralone (Compound 3). ##STR10## Reduction with sodium borohydride leads to the trans 2-amino-1 tetralol (Compound 4). Treatment of Compound 4 with chloroacetyl chloride or a suitably substituted derivative yields the chloroacetamide (Compound 5). (The size of the heterocyclic ring may be increased by substituting chloropropionyl chloride for chloroacetyl chloride.) ##STR11## Reaction of (Compound 5) with sodium hydride or sodium hydroxide leads to ring closure to the lactam (Compound 6). Reduction of this lactam with lithium aluminum hydride gives the amine (Compound 7) in which A is --CH2 --. ##STR12## Alkylation with RI or RBr yields the tertiary amine (Compound 8). This can also be achieved by acylation of Compound 7 with an alkane carboxylic acid chloride followed by reduction with lithium aluminum hydride. (R5 ' is R5 less one methylene unit.) A third alternative is to directly alkylate Compound 7 with a NaBH4 -carboxylic acid complex. On treatment with boron tribromide the methoxy group (--OCH3) of Compound 8 is converted to a phenol (--OH) to yield Compound 9. (The numbering of the carbons corresponds to A=--CH2 --.) ##STR13##
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted with pyrrolidine (3.0 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.44 g of 2-benzyloxy-5-methoxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.44 g, 1.08 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) afforded 0.2 g of the title compound, mp 177-179° C.;
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:14]=[C:5]1[CH2:4][CH:3]([CH2:2][O:1][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][N:6]1[C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10]
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](C(N)=O)N1CC(COc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 ml three necked flask fitted with magnetic stirrer and dropping funnel under inert atmosphere, 1 g (5 mmoles, 1 eq) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 is dissolved in 20 ml of THF and cooled down to 0° C. 517 mg of phenol, 0.87 ml (960 mg) of diethyl azodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmoles, 1.1 eq each) are successively added and the mixture stirred for 2 hours. The mixture is concentrated to dryness and purified by Prep LC (500 kg SiO2, CH2Cl2/EtOH, 97.5:2.5) to give 1.1 g of pure 18, 80%, crystallised from ethyl acetate.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)=[CH:7][CH:6]=1)[NH2:4].C(O[CH:21](OCC)[CH2:22][CH2:23][C:24]#[N:25])C>O>[C:24]([CH2:23][CH2:22][CH:21]=[N:4][NH:3][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)=[CH:7][CH:6]=1)#[N:25]
Reactant: CCOC(CCC#N)OCC
Reactant: NNc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: Cl
Solvent: O
Product: N#CCCC=NNc1ccc(C[C@H]2COC(=O)N2)cc1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
1M aqu. HCl (4.0 ml) was added to a solution of the product from step (a) (2.4 g) in water (35 ml). 3-Cyanopropanal diethylacetal (Aldrich, 1.7 g) was added at room temperature and the mixture stirred for 2 hours. Further acetal (0.20 g) was added and the mixture stirred for another 20 minutes. The aqueous phase was decanted from the resulting gum and extracted with ethyl acetate. The extracts were combined with the gum and evaporated in vacuo to give the desired product (2.5 g).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)=[O:3])[CH3:6]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)N1CCS(=O)(=O)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1 mL, 9.27 mmol) was reacted with thiomorpholine 1,1-dioxide (1.1638 g, 8.61 mmol) and pyridine (783 mg, 801 μl, 9.9 mmol) in methylene chloride (15 mL) at room temperature for 3 h to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester. A portion of 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester (577 mg, 1.614 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.5 mg, 0.244 mmol) in the presence of cesium carbonate (598.4 mg, 1.84 mmol) in dimethylformamide (7 mL) overnight to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-ethyl ester as an off-white solid (175.3 mg, 87% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O8S: [(M+H)+]: 821, found: 821
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (2.01 g, 11.55 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (0.924 g, 23.10 mmol). The reaction mixture was stirred for 1 h at room temperature. To this, (2-(chloromethoxy)ethyl)trimethylsilane (2.89 g, 17.33 mmol) was added slowly. The reaction mixture was stirred overnight. LCMS—0.26 min, MH+ 304.1 (non-polar method). The reaction was quenched with sat. aq. NH4Cl, and then diluted with ethyl acetate. The reaction mixture was extracted with EtOAc. The combined organics were washed with water and brine, then dried over sodium sulfate, filtered off and concentrated in vacuo. The crude product was purified by flash chromatography column using 0-50% EtOAc/heptane. 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one was obtained as a yellow viscous liquid. LCMS (m/z): 304/306 (MH+), 0.95 min.