Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1.[N-:18]=[N+:19]=[N-:20].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:18]([CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1)=[N+:19]=[N-:20]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CBr)O2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CN=[N+]=[N-])O2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
2-Bromomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline7-one (4.90 g, 16.7 mmol) and sodium azide (7.5 g, 115 mmol) were added to dimethylformamide (150 ml), and the mixture was stirred in a bath of 100° C. for 1.5 hours, followed by cooling and condensing. The residue was combined with chloroform, and washed with water. The washed material was dried and condensed. The resultant residue was recrystallized from chloroform--n-hexane. As a result, 4.12 g of 2-azidomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one was obtained as brown prisms (96.6%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:20]=1)C=O>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([OH:9])[CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1c(C=O)cc(Br)cc1C(C)(C)C
Solvent: ClCCl
Product: COCOc1c(O)cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
After adding 70% mCPBA (25 g) to a solution of 5-bromo-3-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (30 g, 97 mmol) in methylene chloride (200 ml), the mixture was stirred at 50° C. for 2 hours. The organic layer was washed with a saturated sodium thiosulfate solution and saturated sodium hydrogencarbonate solution and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (17 g) as a light yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:28][C@@H:15]3[O:16][CH:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[O:18][CH2:19][C@@H:14]3[CH2:13]2)[CH:3]=1.CCN(C(C)C)C(C)C.[C:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])#[CH:39]>CN(C=O)C.[Cu]I.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>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:17]2[O:16][C@H:15]3[CH2:28][C@H:12]([N:4]4[C:5]5[N:6]=[CH:7][N:8]=[C:9]([CH3:11])[C:10]=5[C:2]([C:39]#[C:38][Si:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3]4)[CH2:13][C@H:14]3[CH2:19][O:18]2)=[CH:21][CH:22]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(I)c5c(C)ncnc54)C[C@@H]3O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(C#C[Si](C)(C)C)c5c(C)ncnc54)C[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a suspension of 5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (337 mg, 0.685 mmol), copper(I) iodide (26.0 mg, 0.137 mmol), dichlorobis(triphenylphosphine)-palladium(II) (48.0 mg, 0.0684 mmol) and DIPEA (0.240 mL, 1.38 mmol) in DMF (20.0 mL) was added ethynyltrimethylsilane (188 mg, 1.91 mmol) and the mixture was stirred at rt overnight. The reaction mixture was quenched via addition of saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 75% EtOAc in hexanes afforded the title compound (314 mg, 99%). LC/MS: Rt=2.38 min, ES+ 462 (AA standard).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15](Cl)[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15]([NH:36][CH2:34][CH3:35])[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)S(=O)(=O)n1c(Cl)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Solvent: C1CCOC1
Product: CCNc1nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc2n1S(=O)(=O)C(C)C
Yield: 84 %

Procedure:
Prepare essentially as described in the previous preparation (Preparation 97) starting from 2-(tert-butyldimethyl-silyloxy)-1-[2-chloro-3-(propane-2-sulfonyl)-3H-benzimidazol-5-yl]-2-phenyl-ethanone (760 mg, 1.50 mmol), ethyl amine (0.25 mL, 4.50 mmol, 3 equiv) in 2 mL of THF. Yield: 84%. MS(ES+): m(z=516.3 (M+H)+
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1([NH:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.[CH3:15]N>>[ClH:1].[CH3:2][O:3][C:4]([C:6]1([NH:12][CH2:13][CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CNC1(C(=O)OC)CCCCC1
Reactant: CN
Agent: Cl
Product: CCNC1(C(=O)OC)CCCCC1

Procedure:
1-Ethylaminocyclohexane-1-carboxylic acid methyl ester hydrochloride was prepared by the same methods as 1-methylaminocyclohexane-1-carboxylic acid methyl ester hydrochloride, substituting ethylamine hydrochloride for methylamine hydrochloride, in the first step.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1>O>[CH:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:1]([CH2:6][CH2:7][CH2:2][CH2:3][NH2:4])=[O:9])[CH:7]=1
Reactant: CCOC(=O)c1cccnc1
Solvent: O
Product: NCCCCC(=O)c1cccnc1

Procedure:
The first crop of solid was recrystallized by adding it to about 200 mL of hot isopropyl alcohol and adding 6M HCl slowly to the boiling mixture until all of the solid dissolved (about 5 mL of HCl was added). After cooling the solution in the refrigerator, 3.26 g of anabaseine dihydrochloride was collected (mp 175°-180° C., decomp). Anabaseine dihydrochloride was prepared in 56% overall yield based on the moles of ethyl nicotinate used. Since the dry crystalline solid product is not hygroscopic, but the wet solid may pick up water after filtration, filtration should be performed, for example, under nitrogen atmosphere.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([NH2:38])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:17][CH2:18][CH:19]([NH:38][CH2:41][CH2:40][C:39]#[N:42])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(N)COCCCCCCCCCCCCCCCC
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)NCCC#N
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 1,3-di(n-hexadecyloxy)-2-aminopropane (500 mg., 0.93 mmoles), acrylonitrile (75 ml.) and 2 wt. % aqueous sodium hydroxide solution (75 ml.) was heated to 60° C. Tetrabutyl ammonium hydroxide (1 ml. of 40 wt. % aqueous solution) was then added and the resulting mixture stirred for 15 minutes at 90° C. The reaction mixture was then cooled, causing precipitation of solids, which were isolated by filtration and found (TLC) to contain a large quantity of unreacted starting material. Using fresh acrylonitrile and aqueous sodium hydroxide solution in each cycle, the solids were treated two more times by the above procedure. The third cycle solid product was purified by silica gel chromatography (elution with toluene:ethyl acetate) [200 mg., 36% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDCl3) δ 3.07 (t, 2, --NHCH2CH2CN) and 2.53 (t, 2, --NHCH2CH2CN)].
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[CH3:9][Mg]Br>C1COCC1>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]([OH:8])[CH3:9]
Reactant: C[Mg]Br
Reactant: Cc1scnc1C=O
Solvent: C1CCOC1
Product: Cc1scnc1C(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a 0° C. solution of 5-methyl-1,3-thiazole-4-carbaldehyde (1.0 g, 79 mmol) in anhydrous THF (30 mL) was added a solution of methyl magnesium bromide (3M in diethyl ether; 6 mL, 18 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the mixture was then quenched with a saturated solution of ammonium chloride (20 mL). The mixture was extracted with EtOAc (3×30 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 1-(5-methyl-1,3-thiazol-4-yl)ethan-1-ol (1.0 g, 63%). The product was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][N:10]1[C:14](=[O:15])[C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]1=[O:20]
Reactant: OC[C@H]1COCCO1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1COCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL of dry THF and the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to the above mixture dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temp overnight. Next day, the reaction was done. It was concentrated in vacuo to an oil and then purified on flash column chromatography using ethyl acetate/hexane 20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione (2L). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H) 3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98, 3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H) 7.81-7.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CNCc2cc(OC)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)CNCc2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc21
Temperature: 130 °C

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.095 g, 0.0004 mol), (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (0.127 g, 0.000367 mol), p-toluenesulfonic acid monohydrate (0.17 g, 0.00089 mol) and isopropyl alcohol (4 mL). The mixture was heated in a microwave at 130° C. for 30 min. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with DCM/10% ammonia/methanol (10-1) giving the product as tan solid (0.041 g, 19%). Mp 179-184° C.; LCMS (m/e) 545 (M); 1H-NMR (DMSO, 400 MHz) δ 9.43 (s, 1H), 8.40-8.36 (d, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.55-7.48 (t, 1H, J=7.32 Hz), 7.32-7.29 (t, 1H, J=7.83 Hz), 7.04 (s, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.55-3.40 (m, 3H), 3.03 (s, 2H), 1.23-1.14 (d, 6H, J=6.82 Hz), 0.90-0.86 (t, 3H, J=7.08 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CCO>[CH3:25][O:24][C:22]([C:21]1[C:20]([CH:17]2[CH2:19][CH2:18]2)=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:23]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
In a 5 ml round-bottomed flask, (2-amino-5-chlorophenyl)(phenyl)methanone (100 mg, 432 μmol, Eq: 1.00) and methyl 3-cyclopropyl-3-oxopropanoate (79.8 mg, 561 μmol, Eq: 1.3) were combined with EtOH (1.5 ml) to give a light yellow solution. Ytterbium triflate (26.9 mg, 43.2 μmol, Eq: 0.1) was added. The mixture was stirred at room temperature overnight, upon which a white precipitate formed. The precipitate was filtered and washed with ethanol to provide the title compound (67 mg, 46%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 4-bromo-benzaldehyde (5 g) and ethyl cyanoacetate (2.9 mL) in toluene (50 mL) was added piperidine (0.046 mL), and the mixture was stirred at reflux for 2 h with a Dean-Stark separator. The mixture was cooled to rt, stirred overnight and toluene was evaporated in vacuo. The crude residue was crystallized from EtOAc to yield the title compound (6.77 g, 90%) as a light yellow solid, MS (EI): m/z=279 ([M]+, 1Br).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)Cl.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([O:29][CH:30]([O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH3:31])[CH3:28]
Reactant: C=C(C)C(=O)O
Reactant: CCOCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC(C)OCC
Yield: 96 %

Procedure:
In a flask having four inlets, 15.1 grams (0.21 mols) of ethylvinylehter and 20 grams (0.23 mols) of methacrylic acid were dissolved into 200 ml of methylene chloride. Then, 0.53 grams (0.0021 mols) of p-toluenesulfonic acid pyridine salt was added to the mixture, and stirred for complete dissolution of p-toluenesulfonic acid pyridine salt into the mixture. The resultant solution was stood at room temperature for six hours. Then, 200 ml of diethylether was added into the solution. The resultant solution was washed three times with 2.5% aqueous sodium hydroxide, and further six times with water. Then, an ether layer was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, a methylene chloride layer was evaporated. As a result, there was obtained 31.8 grams of 1-ethoxyethylmethacrylate. The yield was 96%. With respect to a structure of the target material, IR was measured with an analyzer, IR-470 model available from Shimazu Seisakusho, and 1H-NMR was measured with an analyzer, AMX-400 model available from Bruker Instruments.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH:27][C:28](=[O:31])[CH2:29]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:17]=[C:16]2[C:15](=[CH:20][CH:19]=1)[N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:29][C:28](=[O:31])[NH:27]2)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(NC(=O)CBr)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1ccc2c(c1)NC(=O)CN2C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 4-[4-allyloxycarbonyl-2-(2-bromo-acetylamino)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (23.0 g, 46.33 mmol, 1.0 equiv) and N-ethyldiisopropylamine (11.98 g, 92.67 mmol,2.0 equiv) in toluene (250 mL) was heated to reflux. After 8 h, the reaction mixture was cooled, washed with water and concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with dichloromethane/acetone (95:5) to obtain 10.0 g (52%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.65 (br s, 4H), 2.89 (s, 2H), 3.74 (s, 2H), 3.90 (br s, 1H), 4.05 (br s, 2H), 4.73 (d, J=5.1, 2H), 5.25 (d, J=10.4, 1H), 5.36 (dd, J=17.2 Hz, J=1.1 Hz, 1H), 5.98-6.05 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 7.44 (d, J=1.4 Hz, 1H), 7.53 (dd, J=17.2 Hz, J=1.1 Hz, 1H), 10.58 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 26.87, 28.02, 45.15, 53.36, 64.35, 78.67, 110.81, 115.77, 117.36, 118.04, 125.21, 126.61, 132.95, 132.99, 138.63, 153.70, 164.94, 165.00. MS (ISP): 416.2 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:19])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]C1C=CC=CC=1C(CC(=O)C)=O>>[Cl:21][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:19])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])=[O:8]
Reactant: CC(=O)CC(=O)c1ccccc1Cl
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C
Product: Cc1c(C(=O)c2ccccc2Cl)c(NC(=O)CI)cn1C

Procedure:
This compound was prepared by following the procedures described in example (A), steps (a), (b), and (c) but starting from (2-chlorobenzoyl)acetone instead of benzoylacetone. M.p. 155°-57° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][CH2:10][C:11](=N)OC>C(Cl)Cl>[Cl:9][CH2:10][C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=N)CCl
Reactant: Nc1ccccc1S
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of 2-aminothiophenol (8.3 g) in methylene chloride at 0° C. is added methyl chloroacetimidate hydrochloride1 (8.6 g). The reaction is allowed to warm to room temperature while stirring overnight. The mixture is washed with water (3X); dried over MgSO4 and concentrated to an oil. The oil is distilled (120°-135° C. at 0.5 mm Hg) to give 7.8 g (71% yield) of product.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Rh]>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:15]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C#CCO)ncc1Cl
Reactant: [H][H]
Agent: [Rh]
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ncc1Cl
Yield: 62.8 %

Procedure:
A stirred suspension of N-(1-adamantylmethyl)-5-chloro-2-(3-hydroxy-1-propynyl)isonicotinamide (Example 1 (iii)) (0.48 g) and 5% rhodium on carbon (0.020 g) was stirred under a positive pressure (3 barr) of hydrogen until no further uptake was observed. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.305 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]3[CH2:20][CH:15]2[C:16](=[O:21])[O:17]3)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:22][CH2:23][N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].[OH2:31]>>[CH:25]([N:24]([CH:28]([CH3:30])[CH3:29])[CH2:23][CH3:22])([CH3:27])[CH3:26].[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]([OH:17])[CH2:20][CH:15]2[C:16]([OH:21])=[O:31])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Reactant: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Temperature: 40 °C

Procedure:
To a solution of 25 (800 mg, 2.73 mmol) in water (15 mL) in a 20 mL microwave reaction vessel was added DIPEA (1.2 mL, 6.8 mmol) and a stirrbar. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. After 1 min of pre-stirring, the reaction was irradiated for 40 min to a set temperature of 100° C. After cooling to 40° C., the transparent solution was concentrated in vacuo, and the residual brown oil co-evaporated 3× with MeCN to remove any residual water. The crude title compound, in the form of a DIPEA salt, was immediately taken forward to the next step. LC/MS>95%, m/z (ESI+)=312 (MH+).
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.C(OC([N:35]1CCCC1COC1C=NC=CC=1)=O)(C)(C)C>>[N:35]1[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]3=[O:27])(=[O:15])=[O:16])[CH:7]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cccnc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Yield: 82 %

Procedure:
5-(2-(Pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (20) was prepared according to the same procedure for compound 10, except using compound 19, and the crude product was recrystallized from ethyl acetate to afford 1.75 g (82%) of 20 as a yellow solid, mp 215.9-217.8° C. 1H NMR (300 MHz, DMSO) δ 11.42 (s, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.16 (d, J=4.5 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.38 (m, 1H), 7.33 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 4.15-4.02 (m, 2H), 3.90 (m, 1H), 3.34 (m, 1H), 3.12 (m, 1H), 1.87 (m, 2H), 1.67-1.54 (m, 2H). LCMS m/e: 387.8 (M+H). Anal. Calcd for C18H17N3O5S.0.5H2O: C, 54.54, H, 4.58; N, 10.60. Found: C, 54.56, H, 4.70; N, 10.04.