Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH3:23])[CH3:22]
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C)c(C)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3,4-Dimethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53]Cl)=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:51])(=[O:43])=[O:44]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (720). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:19]([CH2:18][CH2:17][O:16][CH3:15])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: COCCN
Solvent: CC(=O)O
Product: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 2-methoxyethylamine (0.20 mmol, 15 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CC#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 4-methoxyphenylacetonitrile (200 g, 1.36 mol) and tetrahydrofuran (500 mL). Cool to about −5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (2900 mL, 1 M in tetrahydrofuran, 2.90 mol). When the addition is complete warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−12° C.) solution of ethyl bromoacetate (459.9 g) in tetrahydrofuran (1800 mL) at such a rate that the temperature of the reaction mixture does not rise above about 15° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether and extract with water, 10% hydrochloric acid solution, and saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 175-185° C. at 1.0 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[CH2:20]([Mg]Br)[CH3:21]>O1CCCC1.CCOCC>[CH2:20]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:21]
Reactant: CC[Mg]Br
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 M ethylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [I-].C1([C:8]([PH3+])([C:15]2[CH:20]=C[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(C)(C)C.[K+].[C:28]([N:35]1CCCC(=O)C1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:18][CH2:17][CH2:16][C:15](=[CH2:20])[CH2:8]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Triphenylmethyl phosphonium iodide (22.14 g) and toluene (135 ml) are added into a three mouth flask (500 ml), stirred at room temperature to obtain a milky white suspension and quickly changed to orange after potassium tert-butanolate (5.31 g) is added. Then N-Boc-3-piperidone (6.0 g) in toluene (66 ml) is added into a constant pressure funnel and dropped into the flask under argon with obvious exothermic phenomenon, and kept at the temperature of 30° C. and the reaction is tracked by TLC after addition. After reaction, the mixture is filtered and washed with a saturated brine (200 ml, 2 times) and then adjusted to pH≈3 with diluted HCl (1M), and then washed with a saturated brine to pH=7, dried with anhydrous sodium sulfate, and filtered to obtain a yellow transparent liquid. The yellow transparent liquid is purified together with silica gel by chromatography (elution liquid: petroleum ether:ethyl acetate=15:1) to obtain a yellow oil-liquid of N-Boc-3-methylene piperidine (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: COc1ccc(C)cc1C(O)=S
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[O:44][CH:45]=[CH:46][N:47]=2)=[CH:38][C:37]=1[CH3:48]>>[CH3:48][C:37]1[CH:38]=[C:39]([C:43]2[O:44][CH:45]=[CH:46][N:47]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ncco2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncco6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenyl)oxazole following a procedure analogous to that described in Step 2 of Intermediate 17. LC (method 11): tR=1.27 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:36]1([C:42]2[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=2[C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(C2C=CC=CC=2)C(C(O)=O)=CC=CC=1>C1COCC1.O>[OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C(O)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a cold (ice-bath) solution of 2-(2-hydroxyethyl)-5-(4-aminobenzyl)-1,5-benzothiazepine-4-one as prepared in Example 21 (0.865 g, 2.6 mM) in dry THF was added N,O-bis(trimethylsilyl)acetamide (1.16 ml, 5.2 mM). After 1 hour, 2-phenylbenzoyl chloride (0.570 g, 2.6 mM), prepared from 2-biphenylcarboxylic acid as described in Example 3, was added and stirring was continued for an addition hour. Water (80 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extract was dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH2Cl2) yielded the desired product as a white solid (1.1 g, 83%) m.p.116-120° C. 1H NMR (300 MHz, DMSOd6) δ7.8 (d, J=7 Hz, 1H); 5.09(d, J=15 Hz, H); 4.89(d,J=15 Hz,1H); 3.79 (m, 3H); 2.69-2.24(m, 2H); 1.71 (m, 2H); m/z (MH+)509.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:37]1([C@H:47]([NH2:49])[CH3:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([NH:49][C@@H:47]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[CH3:48])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1COCC(=O)N1Cc1ccccc1)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a stirred solution of 4-benzyl-5-oxomorpholine-3-carboxylic acid (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580) (500 mg, 2.12 mmole) in dichloromethane (15 mL), HOBt (430 mg, 3.19 mmole) and DIPC (287 μL, 3.19 mmole) were added at room temperature. The reaction mixture was stirred for 15 min, then (R)-1-(naphthalen-1-yl)ethanamine (400 μL, 2.57 mmole) was added to the reaction mixture and stirred overnight. Solid separated out was filtered, washed with dichloromethane (2×15 mL), filtrate collected and washed with brine solution (2×15 mL) and DM water. The organic layer was concentrated to get crude amide and which was further purified by flash chromatography (n-Hexane:ethyl acetate, 8:3) to get title compound (500 mg). m/z 389.2
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O.O>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.07 h

Procedure:
9α-Hydroxyandrostenedione (20.00 g.) is dissolved in methylene chloride (150 ml.) and cooled to -19°. Chlorosulfonic acid (10 ml.) is added while maintaining the temperature at less than or equal to -9°. After only a few minutes the reaction is shown to be nearly complete as measured by TLC. Additional chlorosulfonic acid (1 ml.) is added. Water (50 ml.) is added to the reaction mixture with the temperature rising from -18° to -1°. The phases are separated and the aqueous phase is extracted with methylene chloride (125 ml.). The organic phase is washed with aqueous sodium bicarbonate solution (10%, 50 ml.). The aqueous phases are combined and back extracted with methylene chloride. The organic phases are combined and concentrated under vacuum to approximately 80 ml. at a temperature of about 20°-23°. Heptane (100 ml.) is added and the mixture stirred for approximately 4 minutes at approximately 19°. The mixture is concentrated under vacuum to approximately 100 ml. at a temperature of about 25°-30°. Heptane (50 ml.) is again added and the mixture again concentrated to approximately 100 ml. The mixture is cooled to 25° and stirred for 15 minutes, filtered, and the crystalline material washed with heptane (25 ml.) and dried under vacuum at 50° to give androsta-4,9(11)-diene-3,17-dione, 17.96 g. (89.8% weight yield, 95.3% chemical yield); m.p. 197.5°-203.5°; [α]D +220° (chloroform); UV (methanol) λmax = 240 nm (ε = 16,200).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:20][NH:21][CH3:22]>CO>[CH3:20][N:21]([CH3:22])[CH2:3][CH2:2][C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Reactant: CNC
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CCC2
Temperature: 65 °C

Procedure:
1-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (crude from previous reaction, assumed 0.91 mmol) was dissolved in methanol (5 mL), treated with excess dimethyl amine (5.0 mL, 10 mmol, 2 M in THF, Aldrich), and the reaction heated in a sealed tube at 65° C. for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was separated and then back-extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-3-oxo-1-propanamine which was taken directly to the next step without determination of yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.94 (m, 2 H), 2.18 (bs, 6 H), 2.56-2.71 (m, 4 H), 2.80 (t, J=6.4 Hz, 2 H), 3.71 (t, J=6.0 Hz, 2 H), 3.90 (s, 3 H), 7.20 (s, 1 H), 8.27 (very broad singlet due to amide rotomers, 1 H); ESIMS (M+H)+=308.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH2:18]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CN1CCCC1=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:29][CH:28]([OH:30])[CH2:27][O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Reactant: CCCCCCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Product: CCCCCCCCOCC(O)COc1ccc(-n2nc3ccccc3n2)c(O)c1

Procedure:
A mixture of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole (7.0 grams, 0.031 mole), 3-n-octyloxy-1,2-epoxypropane (10.7 grams, 0.046 moles), N-methyl-2-pyrrolidone (40 ml) and ethyltriphenylphosphonium bromide (0.2 gram) was heated for four hours at 135°-150° C. The solvent and excess epoxide were then removed by distillation. The resulting residue was dissolved in methylene chloride, washed with hydrochloric acid, water and sodium chloride solution before passing through a silica gel column. The product was obtained as a yellow oil which crystallized on standing. Recrystallization from heptane gave the above named product with a melting point of 51°-55° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH2:46])[CH:26]=[CH:27][C:28]=1[C:29]1[O:30][C:31]([C:34]2[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:36][O:37][C:38]=2[CH3:39])=[N:32][N:33]=1>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:46][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:26]=[CH:27][C:28]=1[C:29]1[O:30][C:31]([C:34]2[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[N:36][O:37][C:38]=2[CH3:39])=[N:32][N:33]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccsc2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 72 h
Yield: 50.8 %

Procedure:
To a solution of 3-thiophenecarboxylic acid (162 mg, 1.26 mmol) in dichloromethane (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol). After stirring for 2 min 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (400 mg, 1.15 mmol) was added and stirring was continued for 3 d at ambient temperature. The reaction mixture was extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mL. Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (268 mg, 51%) as a white solid. MS: m/e=459.2 [M+H]+.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CN(C)C=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:23][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:17][CH:18]=1
Reactant: Nc1ccc(N)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (203 mg, 1.0 mmol) in N,N-dimethylformamide (2.5 mL) is added 1,4-phenylenediamine (108 mg, 1.0 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to ambient temperature, product precipitated out of solution. The product is recovered by filtration, rinsing with diethyl ether, and drying to yield 205.9 mg 4-[(4-Amino-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N:5]2[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nn(-c2cccc(OC)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.9 g, 46%) as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:17]=3)[CH2:13][C:12]2=[O:30])[CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[CH:25]1([O:24][C:18]2[CH:17]=[C:16]([CH:14]3[CH2:15][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:31])=[O:3])[C:12](=[O:30])[CH2:13]3)[CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CC(=O)N(c3cccc(C(=O)O)c3)C2)cc1OC1CCCC1
Temperature: 90 °C
Yield: 89 %

Procedure:
3-[4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzoic acid ethyl ester (180 mg, 0.43 mmol) was mixed with EtOH:water (1:1, 20 mL) and NaOH (1N, 1.3 mL). The mixture was heated to 90° C. for 12 h and then cooled down to r.t. After neutralizing to pH=2 with HCl (1N), the mixture was extracted twice with EtOAc. The organic layer was combined, washed with brine and dried over MgSO4. After concentration 150 mg of the desired product was obtained as a light brown solid. Yield: 89%.