Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)=O>C(Cl)(Cl)Cl.O>[CH:1]1([NH:4][CH2:23][C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]#[C:34][C:35]3[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Cyclopropylamine (99 μL), acetic acid (27 μL) and sodium triacetoxyborohydride (0.10 g) were added to a chloroform (4.0 mL) suspension of 1-formyl-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (0.20 g) as obtained in Example 23-(3), and the mixture was stirred for 1 hour and 10 minutes at room temperature. Sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1 hour and 15 minutes at room temperature. Further, sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1 hour and 15 minutes at room temperature. Water and chloroform were added to isolate the organic layer, and the extract was washed with water and brine sequentially. The washed extract was dried over anhydrous sodium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=50/1→10/1) to obtain 1-[(cyclopropylamino)methyl]-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (orange oil) (0.18 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:15]2[CH2:17]O2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:23]([N:25](CC)CC)C.CS(Cl)(=O)=O.CN>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:15]([NH:25][CH3:23])[CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: c1ccc(COc2cccc([C@H]3CO3)c2)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: O
Product: CN[C@H](CN1CCCC1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Example 3 (2.80 g, 12.4 mmol) in ethanol (45 mL), pyrrolidine (3.3 mL, 39.5 mmol) was added. The reaction was heated to reflux for 2.5 hours then all volatiles removed in vacuo. This was then dissolved in diethyl ether (60 mL), cooled to 0° C., and flushed with argon. Triethylamine (5.5 mL, 39 mmol) was added followed by methanesulphonyl chloride (1.2 mL, 16 mmol), and the reaction was stirred for 30 minutes. More triethylamine (3.7 mL, 26 mmol) was added, the reaction was warmed to room temperature over 30 minutes, then an aqueous solution of methylamine (40% w/w) (19 mL, 220 mmol) and water (16 mL) were added. After stirring for 18.5 hours, the layers were separated, and the aqueous layer was extracted with diethyl ether (3×100 mL). The combined organics were washed with 5% sodium bicarbonate solution (60 mL), water (60 mL) and brine (60 mL), dried (MgSO4), and the solvent removed in vacuo. Purification by column chromatography (dichloromethane:methanol 9:1→dichloromethane:methanol:ammonia 40:9:1) gave the product as a yellow semi-solid, 9.0 mmol, 72%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH:10]=[CH:11]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:11][CH2:10][CH:9]([CH2:14][CH2:13]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1
Reactant: CCOC(=O)N1C2C=CC(CC2)C1c1cccnc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N1C2CCC(CC2)C1c1cccnc1
Yield: 98 %

Procedure:
A solution of the (±)-endo and (±)-exo isomers of 3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]oct-5-ene, compound (II), (750 mg, 2.90 mmol) in glacial acetic acid (0.5 mL) and Pd/C (10%) was shaken under a H2 atmosphere in a Parr apparatus for 2 hours. The catalyst was removed by filteration over a bed of Celite and the filterate was basified by addition of a solution of 40% of NaOH in water. The aqueous basic solution was extracted with dichloromethane (4×20 mL) to give 740 mg (98%) of compound (XII).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[O:14]1[CH2:19][CH2:18][N:17](CCN)[CH2:16][CH2:15]1.[OH-].[Na+].[C:25](#[N:27])[CH3:26]>O>[NH:17]1[CH2:16][CH2:15][O:14][CH:19]([CH2:26][CH2:25][NH:27][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:18]1
Reactant: C=CC(=O)Cl
Reactant: CC#N
Reactant: NCCN1CCOCC1
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)NCCC1CNCCO1
Reaction time: 3 h

Procedure:
In a 1 liter capacity round bottom flask equipped with a stirrer were put 90.5 g (1.0 mole) of acrylic acid chloride and 250 cc of acetonitrile and, as a polymerization-inhibitor, 0.5 g of hydroquinone, and the contents were cooled to 5°-10°C, and thereafter, 130 g (1.0 mole) of 2-morpholinoethylamine were added dropwise thereto in the course of 3 hours while stirring. Afterwards, the contents were stirred further for 2 hours at 40°-50°C. Next, the temperature of the reaction mixture was reduced to 15°-30°C and a solution of 40 g of sodium hydroxide in 100 cc of water was added thereto and the mixture then was stirred for 30 minutes. After removal of the sodium chloride which separated, 97.0 g (52.7%) of a fraction of 122°-124°C/0.05 mmHg were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[Cl:31][CH2:32][CH2:33][O:34][CH2:35]CO>>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:35][O:34][CH2:33][CH2:32][Cl:31])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: OCCOCCCl
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCOCCCl)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 58 %

Procedure:
A solution of mitomycin A (100 mg) in 2 ml of 2-(2-chloroethoxy)ethanol was stirred at room temperature and under nitrogen for 45 minutes with 300 mg of a 1.6% solution of KOH in 2-(2-chloroethoxy)ethanol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction product was chromatographed on a silica gel column using first chloroform, which elutes the 2-(2-chloroethoxy)ethanol and then acetone, which elutes the product. The latter was purified twice by preparative thin layer chromatography on silica gel using chloroform as a solvent in the first purification and chloroform-acetone 1:1 in the second purification. This procedure gave 74 mg (58%) of the title compound, having a melting point of 101°-104° C. (decomposition) and providing the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:24]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(OCC)(=O)C>[Pt]=S.CO>[NH2:24][C:4]1[C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:23])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[CH2:12][CH2:13]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3[N+](=O)[O-])CC2)n1
Agent: S=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
A round bottom flask is charged with 5% platinum sulfide on carbon (0.200 g, 0.039 mmol). The flask is evacuated and refilled with argon three times. To the flask is added 1-[4-(5-chloro-3-nitro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (1.10 g, 2.90 mmol) as a solution in a 1:1 mixture of ethyl acetate:methanol (100 mL). The mixture is placed under an atmosphere of hydrogen and stirred for 5 h at room temperature. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.67 g of 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone as a white solid in 66% yield.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH:19]([C@H:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35])=O>C1COCC1>[O:27]=[C:23]1[CH2:24][CH2:25][CH2:26][C@H:21](/[CH:19]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35]
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 18 mg, 0.45 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (110 mg, 0.45 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile (0.50 mmol, crude from step 5) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→40% EtOAc/CH2Cl2, gradient) afforded 75 mg (48%) of the title compound.
Reaction SMILES: C[I:2].[CH3:3][N:4]([CH2:6][C:7]1[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:5].[C:14](OCC)(=O)C>C(O)C>[I-:2].[CH2:12]([N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N+:4]([CH3:14])([CH3:3])[CH3:5])[CH3:13]
Reactant: CCn1cccc1CN(C)C
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CCO
Product: CCn1cccc1C[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Methyl iodide (7.7 mL, 124 mmol) was added to a solution of 2-(N,N-dimethylaminomethyl)-1-ethylpyrrol (15.6 g, 102 mmol) in ethanol (150 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (150 mL) was added to the reaction mixture and the precipitated crystal was collected by filtration. After the crystal was washed with ethyl acetate and dried to obtain (1-ethylpyrrol-2-yl)methyltrimethylammonium iodide (20.0 g, yield: 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:13]([O:20][C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[N:28]1[S:32](=[O:34])(=[O:33])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:30](=[O:41])[CH2:29]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][C:25]1[CH:24]=[CH:23][C:22]([N:28]2[CH2:29][C:30](=[O:41])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[S:32]2(=[O:34])=[O:33])=[C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [I-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3 g, 46 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (25 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.25 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.3 mL) is added, followed after 30 min with (2-iodoethyl)-carbamic acid tert-butyl ester (4.5 g, 16.5 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.20 g) and tri-o-tolylphosphine (0.30 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[F:10][CH:11]([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:21][CH:11]([F:10])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]1[CH2:2][C:3]1[CH:8]=[N:7][C:6]([F:9])=[CH:5][CH:4]=1)=[O:13]
Reactant: O=C(N=c1cccc[nH]1)C(F)F
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N=c1ccccn1Cc1ccc(F)nc1)C(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
128 mg (0.75 mmol) of 5-bromomethyl-2-fluoropyridine was dissolved in 3 ml of anhydrous DMF, 116 mg (0.68 mmol) of 2,2-difluoro-N-[pyridin-2(1H)-ylidene]acetamide was dissolved in 3 ml of anhydrous DMF and added thereto, and subsequently, 103 mg (0.75 mmol) of potassium carbonate was added thereto and the resulting mixture was stirred at 65° C. for 2 hours. After the reaction was completed, the reaction solution was returned to room temperature, and ethyl acetate and water were added thereto to perform liquid separation. The organic layer was washed with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A small amount of hexane and diethyl ether were added thereto to precipitate crystals, and thus the crystals were collected and dried to obtain the subject material. Amount obtained 50 mg (yield 26%).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1([C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18]N=2)CCCC1.O([CH3:26])[Na]>C1COCC1>[C:19]1([CH:20]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:18]=[CH:26][CH:16]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(N2CCCC2)nc1
Reactant: O=C(CO)c1ccccc1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 65 %

Procedure:
1.85 g (13.6 mmol) of 2-hydroxyacetophenone, 2.0 g of 6-(pyrrolidin-1-yl)nicotinaldehyde (1.34 mmol), and 10 ml of 25% NaOCH3 were reacted in 50 ml of dry THF to give 2.2 g (65%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 13.13 (bs, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.85 (d, J=15.3 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.74 (d, d, J=2.4, 9.0 Hz, 1H), 7.43 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.37 (d, J=15.3 Hz, 1H), 6.98 (d, d, J=0.9, 8.4 Hz, 1H), 6.89 (d, d, d, J=0.9, 7.2, 8.1 Hz, 1H), 6.37 (d, J=9.0 Hz, 1H), 3.49 (bs, 4H), 2.05-1.96 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:44][CH2:43][CH2:42][C@H:38]2[C:39](O)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:39](=[O:40])[C@@H:38]3[CH2:42][CH2:43][CH2:44][N:37]3[S:34]([C:31]3[CH:32]=[CH:33][C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 15.8 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (400 mg, 1.28 mmol) was reacted with N-(4-tert-butylphenylsulfonyl)-L-proline (477 mg, 1.53 mmol) to provide 123 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-[(4-tert-butylphenyl)sulfonyl]-L-prolinamide as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]1(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[NH:16][S:15]1(=[O:23])=[O:24])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CC(C)C1NS(=O)(=O)N(CCl)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C1NS(=O)(=O)N(COC(=O)c2c(Cl)cccc2Cl)C1=O
Yield: 48.9 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid (0.44 g; 2.3 mmol), 2-chloromethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.2 mmol) and triethylamine (230 mg; 2.3 mmol) in toluene was allowed to reflux for 2.5 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (25%-30% ethyl acetate in hexane) to afford 0.41 g (49%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =isopropyl; R3 =H) as a solid, m.p.151°-152° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[CH3:13])[C:5]1=O.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[C:7]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=1)[CH:8]=[CH:9][C:10]=2[CH3:13]
Reactant: Cc1ccc(-c2ccc(C(C)(C)C)cc2)c2c1CC(C)C2=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1=Cc2c(-c3ccc(C(C)(C)C)cc3)ccc(C)c2C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.09 g (55.3 mmol) of sodium borohydride and 18.59 g (55.3 mmol) of 2,4-dimethyl-7-(4′-tert-butylphenyl)-1-indanone (1d) together with 51 ml of toluene were placed in a reaction vessel. At 50° C., 9.8 ml of methanol were added slowly and the reaction mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, 35 ml of 2 N sulfuric acid were added and the mixture was stirred for 30 minutes. After phase separation, the organic phase was washed twice with a total of 60 ml of 2 N sulfuric acid, most of the solvent was removed and the residue was taken up in 200 ml of toluene and admixed with 0.2 g of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 1.5 hours on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. This gave 16.8 g of the desired product (1e).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][O:3][CH2:2]1.[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1>CC(N(C)C)=O.CCOC(C)=O>[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]1=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1COCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCN1C(=O)COCC1=O
Temperature: 120 °C
Yield: 29.3 %

Procedure:
A mixture of diglycolic anhydride (22 g, 0.188 mol), tert-butyl-3-aminopropylcarbamate (65 g, 0.377 mol) and NMM (21 mL, 0.188 mol) in DMA (300 mL) was heated up to 120° C. for 48 h. The reaction mixture was cooled down to r.t and diluted with EtOAc (1.5 L). The solution was washed with brine (5×150 mL), dried with MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel (15% ethylacetate in chloroform) affording 15 g of the title compound (30%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH2:22])[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
Add benzaldehyde (0.24 mol, 26.3 g) to a solution of racemic trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.24 mol, 53.7 g), and acetic acid (92 mL) in ethanol (400 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.49 mol, 31.2 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in a minimum amount of dichloromethane and add 0.1 N aqueous hydrochloric acid to maintain the pH between 4-5. Discard the organic layer. Wash the acidic aqueous layer three times with dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer between 10-12 and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (35.7 g, 46%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 2H), 1.45 (s, 9H), 2.05 (br s 1H), 2.43 (t, 1H), 2.57 (t, 1H), 2.69 (br s, 1H), 3.27 (br s, 1H), 3.70 (d, 1H), 3.94 (d, 1H), 4.15 (br s, 1H), 4.26 (d, 1H), 7.23-7.29 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.36 (m, 2H).
Reaction SMILES: C(#N)N(C)C.[CH3:6][O:7][C:8]([CH:10]1[CH2:16][CH:15]2[C:17](Br)=[CH:18][CH:11]1[C:12](=[O:33])[CH:13]([C:21]([C:23]1[C:24]([CH3:32])=[N:25][C:26]([CH:29]([F:31])[F:30])=[CH:27][CH:28]=1)=[O:22])[C:14]2=[O:20])=[O:9].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]([CH:10]1[CH2:16][CH:15]2[CH:17]=[CH:18][CH:11]1[C:12](=[O:33])[CH:13]([C:21]([C:23]1[C:24]([CH3:32])=[N:25][C:26]([CH:29]([F:30])[F:31])=[CH:27][CH:28]=1)=[O:22])[C:14]2=[O:20])=[O:9]
Reactant: COC(=O)C1CC2C(=O)C(C(=O)c3ccc(C(F)F)nc3C)C(=O)C1C=C2Br
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: CN(C)C#N
Solvent: Cc1ccccc1
Product: COC(=O)C1CC2C=CC1C(=O)C(C(=O)c1ccc(C(F)F)nc1C)C2=O
Temperature: 80 °C

Procedure:
Catalytic amounts (10 mg) of azaisobutyronitrile are added to a solution of 0.10 g (0.24 mmol) of 8-bromo-3-(2-methyl-6-difluoromethyl-pyridine-3-carbonyl)-2,4-dioxo-bicyclo-[3.2.2]non-8-ene-6-carboxylic acid methyl ester (Example 1.1155) and 0.149 ml (0.48 mmol) of tris(trimethylsilyl)silane in 3.5 ml of toluene and the reaction mixture is stirred at a temperature of 80° C. 5 mg portions of fresh azaisobutyronitrile dissolved in a small amount of toluene are then added four times until, after 6 days, the reaction has come to a complete standstill (LC-MS monitoring). The solvent is then removed under reduced pressure and the residue is purified by silica gel chromatography (eluant: gradient mixture of ethyl acetate/tetrahydrofuran/hexane and 3% triethylamine). After removal of the solvents the triethyl-ammonium salt of 3-(2-methyl-6-difluoromethyl-pyridine-3-carbonyl)-2,4-dioxo-bicyclo-[3.2.2]non-8-ene-6-carboxylic acid methyl ester is obtained.