Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.168 g, 0.720 mmol) and 5-fluoroisoindoline hydrochloride (0.138 g, 0.792 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.191 mL, 1.080 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.36 (m, 6H), 6.92-7.02 (m, 2H), 4.85-4.90 (m, 2H), 4.78-4.83 (m, 2H), 4.43 (dd, J=15.6, 1.7 Hz, 1H), 4.06 (d, J=15.7 Hz, 1H), 3.73 (dd, J=7.7, 6.1 Hz, 1H), 3.65-3.71 (m, 1H), 3.57 (dt, J=11.6, 5.8 Hz, 1H), 2.19-2.29 (m, 1H), 1.97-2.11 (m, 2H), 1.83-2.00 (m, 1H); MS (DCI+) m/z 353 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH:3]([CH3:5])[CH3:4].Cl.[CH:15]([N:18]([CH2:22][CH2:23]Cl)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:22][N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)COc1ccccc1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(C)COc1ccccc1OCCN(C(C)C)C(C)C

Procedure:
The compound was prepared as described in Example 1, using sodium (3.45 g; 150 mmole), o-isobutoxyphenol (12.45 g; 75 mmole) and diisopropylaminoethylchloride hydrochloride (15.0 g; 75 mmole) in 200 ml of ethanol. Yield 11.2 g (51%) of product, boiling at 111°-113° C under a pressure of 0.001 mm.Hg, nD25 : 1.4920.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Se](=O)=[O:14]>O1CCOCC1>[O:12]=[C:3]1[NH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=[C:2]1[CH:1]=[O:14]
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2[nH]c1=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2[nH]c1=O

Procedure:
A mixture of 3-methyl-1H-quinoxalin-2-one (0.5 g) and selenium dioxide (0.728 g, 2.1 eq) in dry dioxane (33 mL) was stirred at reflux under nitrogen for 30 min. After cooling, the dark-brown mixture was concentrated under reduced pressure and the residue was purified by FC (AcOEt) to give the title compound as an orange solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:10]=[C:9]([F:17])[CH:8]=1.CN(C)[CH:20]=[O:21]>O1CCCC1>[F:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH3:16])[CH:10]=1)[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: CCCOc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1cc(F)cc(C=O)c1
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Add n-butyl lithium (13 mL, 1.6M, 20.76 mmol) to 1-bromo-3-fluoro-5-propoxybenzene (4.40 g, 18.88 mmol) in tetrahydrofuran (100 mL) cooled in a dry ice/acetone bath over 45 minutes, maintaining the internal temperature <−70°. Stir 30 minutes and add N,N-dimethylformamide (2.76 g, 37.75 mmol). Stir 30 minutes and remove cold bath. After 1 hour, quench with saturated aqueous ammonium chloride. Wash organic layer with water and saturated aqueous sodium chloride. Dry (sodium sulfate), filter and concentrate to an oil. Purify on 120 g silica gel eluting with 0 to 10% ethyl acetate in hexanes to give 2.26 g (65.7%) of the desired compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:21]=[C:22]([O:24]CC3C=CC=CC=3)[CH:23]=2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])[C:3]1=[O:32]>C1COCC1.CO.[Pd]>[OH:24][C:22]1[CH:21]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:32])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reaction time: 16 h
Yield: 109.5 %

Procedure:
A solution of 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)-5-phenylmethoxy-benzamide (Intermediate 19) (449 mg, 1.04 mmol) in THF (10 mL) and methanol (10 mL) containing 10% palladium on carbon (catalytic) was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to afford product (390 mg, 100%). 1HNMR δ (300 MHz, CDCl3) 2.07-2.22 (m, 1H), 2.54 (s, 3H), 2.57-2.70 (m, 1H), 2.97 (s, 3H), 3.38-3.58 (m, 3H), 4.99 (t, 1H), 6.71 (s, 1H), 6.87 (s, 1H), 6.97 (s, 1H), 8.15 (s, 1H), 8.66 (s, 1H), 9.49 (s, 1H); m/z 343 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][C:46]=1[O:47]CC1C=CC=CC=1)[CH2:12][NH:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)=[O:18])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][C:46]=1[OH:47])[CH2:12][NH:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)=[O:18]
Reactant: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCC(=O)NCc1ccc(O)c(O)c1)NCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Succinic acid bis(3,4-dibenzyloxybenzylamide) (300 mg, 0.42 mmol) was dissolved in THF (50 ml) in a pressure bottle and warmed to 35 C to ensure dissolution of the solid. Palladium on carbon (50 mg 10% Pd/C) was added, and the vessel was pressurized with hydrogen (to 3 atm). The reaction was agitated for 1 hour at room temperature, whereupon TLC revealed reaction had gone to completion. The catalyst was removed by filtration, and the solvent removed under reduced pressure to afford DC-0067 as a crude solid (20 mg). This material was recrystallized from toluene and methanol to afford DC-0067.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3[OH:29])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3[O:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](OS(C)(=O)=O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 1 h

Procedure:
A mixture of 1.76 g of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione, 1.11 ml of methanesulfonyl chloride and 5.2 ml of pyridine was stirred for 1 hour under ice cooling, and then for 12 hours at room temperature. Ice-cooled water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 2.01 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [C:1]([C:3]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2].S(=O)(=O)(O)[OH:14].[OH-].[Na+]>C(O)(=O)C>[CH2:8]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=[C:3]2[C:1](=[O:14])[CH3:2])[CH2:5][CH2:6][CH2:7]1
Reactant: C#CC1=CCCCC12CCCC2
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)C1=CCCCC12CCCC2
Temperature: 75 °C
Yield: 294.1 %

Procedure:
A mixture of 6-ethynylspiro[4.5]dec-6-ene (120 g, 0.748 mol) and sulfuric acid (11.6 g) in acetic acid (500 ml) was heated for 2 h at 75° C., poured into ice, treated with 2N aqueous NaOH (10 ml) and extracted twice with MTBE (150 ml). The combined organic phases were treated with 2N aqueous NaOH (pH>7), washed with water (400 ml), with a saturated aqueous solution of NaCl (400 ml), dried (MgSO4), and concentrated. Short-path Vigreux-distillation (0.08 mbar, head temperature: 85-90° C.) of the crude product (125 g) gave 1-(spiro[4.5]dec-6-en-6-yl)ethanone (62 g, 46%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:27].Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33](=[O:34])[C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:26][CH3:27])=[CH:37][CH:36]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-ethoxybenzoyl chloride (0.26 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.28 g, 2.8 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and purified by column chromatography (C18 reverse phase column). The product fractions were combined, concentrated and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethoxy-benzamide as a white solid (0.26 g, 46% yield); mp 269-271° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.75 (96.56%); 1H NMR (DMSO-d6) δ 1.34 (t, 3H, CH3), 1.90-2.08 (m, 1H, CHH), 2.27-2.45 (m, 1H, CHH), 2.55-2.68 (m, 1H, CHH), 2.80-3.03 (m, 1H, CHH), 4.09 (q, 2H, CH2), 4.30 (d, 1H, CHH), 4.41 (d, 1H, CHH), 4.58 (d, 2H, CH2 and CHH), 5.10 (dd, J=4.5, 13.0 Hz, 1H, CH), 6.99 (d, J=8.3 Hz, 2H, Ar), 7.44 (d, 1H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, 1H, Ar), 7.87 (d, J=8.5 Hz, 2H, Ar), 8.99 (t, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.53, 22.49, 31.18, 42.64, 47.12, 51.56, 63.28, 113.92, 122.01, 122.90, 126.19, 127.02, 129.09, 130.30, 142.35, 144.20, 160.92, 165.75, 167.93, 170.98, 172.85; LCMS: MH=422; Anal. Calcd for C23H23N3O5+0.5H2O: C, 64.18; H, 5.62; N, 9.76. Found: C, 64.03; H, 5.45; N, 9.63.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Si:20]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)c1ccc(CO)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: 0 °C

Procedure:
To a solution of 1-[5-(hydroxymethyl)thien-2-yl]ethanone prepared in the above step in DMF (84 ml) was added imidazole (27.11 g) and thereto was dropped under ice cooling tert-butyldimethylchlorosilane (30.01 g). Thirty minutes later, thereto was added ice water (250 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)thien-2-yl]ethanone (46.53 g).
Reaction SMILES: [CH2:1]([O:3]C=O)C.CC[O-].[Na+].[CH3:10][C:11]([CH3:24])([C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH3:12].Cl>C(O)C>[OH:3][CH:1]=[C:14]([O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:13](=[O:23])[C:11]([CH3:24])([CH3:10])[CH3:12]
Reactant: CC(C)(C)C(=O)COc1ccc(F)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.7 %

Procedure:
163 g (2.2 mols) of formic acid ethyl ester were added dropwise to a solution of 136 g of sodium ethylate in 1,500 ml of ethanol at 0° C. 420 g (2 mols) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one were then slowly stirred in at 0° C. After a reaction time of 24 hours at 0° C., the mixture was allowed to warm to room temperature and was subsequently stirred at this temperature for a further 96 hours. The reaction mixture was poured into 5,000 ml of ice-water and the organic phase was separated off by extraction with chloroform. Unreacted starting material could be isolated from this chloroform solution and could be employed again. The aqueous phase was acidified with 10% strength hydrochloric acid, while cooling, and the oil which separated out was taken up in chloroform. The chloroform phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The oil which remained was distilled in vacuo. 170 g (83% of theory, relative to reacted material) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one of boiling point 101°-102° C./0.6 mm Hg (nD20 =1.5132) were obtained. ##STR50##
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C.C1(C)C=CC=CC=1>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:11][CH:10]=1)[NH2:12])[CH3:16]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
19.8 grams of 4-trifluoromethylanthranilic acid are dissolved in 350 ml of anhydrous ethanol and 300 ml of dry toluene. To this solution is added 21.8 grams of anhydrous p-toluenesulfonic acid. The solution is refluxed under an extractor containing a thimble of anhydrous magnesium sulfate for 2 weeks with periodic replacement of the drying agent. The solvent is then removed on a rotary evaporator. The residue is treated with 200 ml of 2N sodium hydroxide. The resultant mixture is extracted thrice with combined 75 ml portions of diethylether. The combined extracts are washed with 2N sodium hydroxide, then distilled water and finally brine. The organic solution is dried over anhydrous potassium carbonate. The drying agent is filtered off, and the solvent is removed on a rotary evaporator. The resultant oil is chromatographed on a filter column of silica gel with chloroform as the eluant. The first fractions contain 4-trifluoromethylanthranilic acid ethyl ester, which is recovered by crystallization. Melting Point: 42°-43° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CC1CCCN1
Product: CC1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and 2-methyl-pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.8-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, 3H, J=6 Hz); MS (DCI) m/z 331 (M+H)+;
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]([O:7][CH2:8][CH2:9][NH:10][C:15]1[N:17]=[C:18]([Cl:19])[N:11]=[C:12]([Cl:13])[N:14]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(=O)OCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To 194 g of 33% 2-aminoethyl methacrylate hydrochloride solution in water being stirred at 0°-5° C. was added 1 l of additional water followed by dropwise addition of a solution of 74 g (0.4 mole) of cyanuric chloride in 400 ml of acetone. To this mixture was added 67.2 g (0.8 mole) of sodium bicarbonate in portions over a 1 hr. period. The mixture was then stirred for an additional hour at room temperature. The reaction was again cooled to 0°-5° C. and the product was collected by filtration and dried in vacuo at room temperature to give 84.6 g. Recrystallization from a solution of 600 ml of benzene and 850 ml of ligroin with carbon decoloration yielded 56.6 g (mp 138°-140° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])(=[O:11])=[O:10].FC(F)(F)C(O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
For two hours, a solution of 430 mg (1.17 mmol) of tert.-butyl 3-[(2,3-dichlorobenzenesulphonyl)methylamino]propionate and 2.0 ml of trifluoroacetic acid in 30 ml of tetrahydrofuran was stirred at room temperature and then evaporated to dryness. About 30 ml of water were added to the residue and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ccccc1-c1ncccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ncccc1N
Temperature: 65 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 2-(2-methoxyphenyl)-3-nitropyridine (34.3 mg, 0.15 mmol) in EtOAc (5.0 mL) was added tin(II) chloride dihydrate (0.17 g, 0.76 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (10 mL), water (10 mL), and brine (10 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 2-(2-Methoxyphenyl)-3-pyridinamine. Mass Spectrum (pos.) m/e: 201.1 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[C:15]#N.C1C[O:27]CC1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[CH:15]=[O:27]
Reactant: N#Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Diisobutylaluminum hydride (1.0 M in toluene, 28 mL, 28 mmol) was added slowly via syringe to a solution of 3-chloro-4-(trifluoromethyl)benzonitrile (3.79 g, 18.4 mmol) in THF (50 mL) at 0° C. The reaction was allowed to proceed for 2 hr, then warmed to ambient temperature and stirred an additional 2 hr. The reaction was then cooled to 0° C., and quenched with 3 M aq HCl (75 mL). The mixture was allowed to warm to ambient temperature, and stirred vigorously for 1.5 hr. The mixture was then transferred to a separatory funnel and diluted with Et2O. The separated organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 15% EtOAc/hexanes eluant; SF40-150 g column) yielded 2.84 g (74%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.21 (s, 1H), 8.12 (d, J=8.1, 1H), 8.07-8.02 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27](N(C2CC2)CC2C=CC(OC)=CC=2)[C:28]2[N:29]([C:31]([C:34]#[N:35])=[CH:32][N:33]=2)[N:30]=1>CO>[Cl:24][C:25]1[CH:26]=[C:27]([N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C:28]2[N:29]([C:31]([C:34]#[N:35])=[CH:32][N:33]=2)[N:30]=1
Reactant: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CO
Product: COc1ccc(CN(c2cccc(C(=O)OC(C)(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
253B was prepared from 253A and a mixture of 1F following the procedure as described in 1G. HPLC: Rt=4.99 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=490.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:21])[CH2:10][CH:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4].C(O)(=O)C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:33][C:32]3[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2C(N)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (208 mg, 0.64 mmol) in anhydrous 1,2-dichloroethane (5 mL) was added acetic acid (0.041 mL, 0.71 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (172 mg, 0.71 mmol) and sodium triacetoxyborohydride (0.205 g, 0.97 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane (45 ml) and water (100 ml) and the aqueous phase was adjusted to pH 9. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (337 mg, 95%). MS m/z 567 (M+ +NH4); 1H NMR (CDCl3) δ 1.40 (d, 3H), 7.14 (s, 1H).