Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCI (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: C(C1C(F)=C(F)C=C(Br)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[C:40]2[O:39][CH:38]([CH2:41][OH:42])[CH2:37][C:36]=2[C:35]([F:43])=[C:34]([F:44])[CH:33]=1.C(N(C(C)C)CC)(C)C.[C:54]1([CH3:64])[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1>CN(C)C1C=CN=CC=1>[CH3:64][C:54]1[CH:59]=[CH:58][C:57]([S:60]([O:42][CH2:41][CH:38]2[CH2:37][C:36]3[C:35]([F:43])=[C:34]([F:44])[CH:33]=[C:32]([Br:31])[C:40]=3[O:39]2)(=[O:62])=[O:61])=[CH:56][CH:55]=1
Reactant: OCC1Cc2c(F)c(F)cc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCc1c(O)c(Br)cc(F)c1F
Agent: CN(C)c1ccncc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(Br)c3O2)cc1
Yield: 35 %

Procedure:
Treatment of 2-allyl-6-bromo-3,4-difluorophenol (5.0 g, 0.020 mol) with 3-chloroperoxybenzoic acid (77%, 8.1 g, 0.036 mol) followed by potassium carbonate (6.94 g, 0.050 mol) generally according to the procedure described for Intermediate 9 afforded (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methanol a brown oil. Treatment of the alcohol with diisopropylethylamine (2.57 g, 0.020 mol), p-toluenesulfonyl chloride (2.28 g, 0.012 mol), and 4-(dimethylamino)pyridine (0.29 g, 2.375 mmol) generally according to the procedure described for Intermediate 45 gave 2.9 g (35%) of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.46 (silica, ethyl acetate:hexanes 1:3); 1H NMR (DMSO-d6) δH 7.73 (d, 2H); 7.50 (dd, 1H); 7.43 (d, 2H); 5.15 (m, 1H); 4.3 (dd, 1H); 4.22 (dd, 1H); 3.45 (dd, 1H); 3.08 (dd, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=O)[CH2:2][OH:3].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=C.Cl.C(OCC)(=O)C.CCCCCC>CCOCC>[CH3:12][O:11][C:7]([CH:8]1[C:2](=[O:3])[CH2:1][O:5][CH2:6]1)=[O:10]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C1COCC1=O
Yield: 53.6 %

Procedure:
To a suspension of Nail (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd. 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J =16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4 Hz). MS calcd. 144; found (EI) 144.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:4]3[C:9]([C:10](=[O:12])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:26][CH:25]=1
Reactant: Nc1cc(=O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2cc(=O)c3cccnc3n2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Yield: 3.4 %

Procedure:
A mixture of 2-amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (50 mg, 0.16 mmol), CsCO3 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80° C. in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2Cl2 (3×), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C 18 Column, 150×20 mm I.D.; first run: 20–80% CH3CN in water, 11 min.; second run: 50–90% MeOH in water, 20 min.) to afford 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+: 410.2.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:35]1[CH:36]=C[C:38]2[N:43](O)N=[N:41][C:39]=2[CH:40]=1.NC1C=NC=CC=1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:5]([C:6]([NH:41][C:39]2[CH:38]=[N:43][CH:36]=[CH:35][CH:40]=2)=[O:8])=[C:4]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of 4-bromo-5-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 35; 100 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.09 ml, 0.49 mmol), HOBT (45.2 mg, 0.30 mmol), 3-aminopyridine (30.1 mg, 0.32 mmol) and EDC (94 mg, 0.49 mmol). The mixture was heated at 50° C. for 5 hours to allow dissolution. The solvent was removed in vacuo and purified by MDAP to yield the title compound as a white solid. 67 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[CH3:25][O:26][C:27](=[O:35])C1C=CC(Cl)=NC=1>>[CH3:25][O:26][C:27](=[O:35])[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1
Reactant: Clc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
6-(2-Phenylchroman-6-yloxy) nicotinic acid methyl ester was prepared as described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-dichloropyridine with 6-chloronicotinic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ: 8.70 (d, 1H, J 2.4 Hz), 8.29 (dd, 1H, J 8.6, 2.4 Hz), 7.47-7.32 (m, 5H), 7.07 (d, 1H, J 8.6 Hz), 6.96-6.88 (m, 3H), 5.14 (d, 1H, J 10.0 Hz), 3.85 (s, 3H), 2.97 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.[C:35]([S:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41]/[C:40]/1=[CH:45]\[C:46]1[CH:50]=[CH:49][N:48]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:47]=1)(=[O:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C.C(OCC)C>[C:35]([S:38][CH:39]1[CH2:44][CH2:43][N:42]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:41]/[C:40]/1=[CH:45]\[C:46]1[CH:50]=[CH:49][N:48]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:47]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCn1ccc(/C=C2\CNCCC2SC(C)=O)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Triethylamine (16.2 ml) and chlorotriphenylmethane (10.91 g) were added to a solution of the racemic (E)-4-(acetylsulfanyl)-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)piperidine hydrogen trifluoroacetate (Example 111-(c), 22.09 g) in N,N-dimethylformamide (150 ml) at 0° C. After the mixture was stirred at room temperature for 2 hours, it was diluted with a mixed solvent of ethyl acetate and diethyl ether (2:1), and the solution was washed successively with water and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=95/5˜30/70) to give racemic (E)-4-(acetylsulfanyl)-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (19.40 g, yield: 86%).
Reaction SMILES: CC(CCC=C(C)C)CCCC(=O)C([O-])=O.O=C(CCC)C(OCCC(C)CCC=C(C)C)=O.C([C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:58])[C:45]([O:47][CH2:48][CH2:49][CH:50]([CH3:57])[CH2:51][CH2:52][CH:53]=[C:54]([CH3:56])[CH3:55])=[O:46])=[CH:40]C=1)(=O)C.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.CC(CCCCCCCCCCCC)C(=O)C(OCCC(C)CCC=C(C)C)=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O>>[CH:41]1([C:44](=[O:58])[C:45]([O:47][CH2:48][CH2:49][CH:50]([CH3:57])[CH2:51][CH2:52][CH:53]=[C:54]([CH3:55])[CH3:56])=[O:46])[CH2:40][CH2:38][CH2:43][CH2:42]1
Reactant: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CC(C)=CCCC(C)CCOC(=O)C(=O)C1CCCC1

Procedure:
MS (EI): 170 (M+, 5); 114 (1); 101 (1); 98 (4); 97 (48); 96 (4); 95 (1); 70 (6); 69 (100); 68 (3); 67 (6); 66 (1); 65 (1); 55 (4); 54 (1); 53 (2); 51 (1); 43 (1); 42 (2); 41 (22); 40 (2); 39 (7); 29 (5); 28 (1); 27 (4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.Br[C:15]1[C:16]([N:18]([CH3:32])[C:19](=[O:31])[C:20]=1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:15]2[C:16](=[O:17])[N:18]([CH3:32])[C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:2]1
Reactant: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a solution of indole (66 mg, 0.21 mmol) dissolved in toluene (1 mL) was added 0.95M ethylmagnesium bromide (0.5 mL, 0.47 mmol) at 40 ° C., and the whole was stirred at 40° C. for 45 minutes. Successively, a solution of 2-bromo-3-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (66 mg, 0.21 mmol) dissolved in toluene (3 mL) was added thereto, followed by stirring under heating and refluxing for 2 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, toluene was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 3-(1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (71 mg, 96.8%) as red solids.
Reaction SMILES: [N+:1]([CH:4]([N+:10]([O-:12])=[O:11])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].[OH-].[Na+].Cl([F:19])(=O)(=O)=O.C(=O)=O>O.CO>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([F:19])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2]
Reactant: C=CCOCC([N+](=O)[O-])[N+](=O)[O-]
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOCC(F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 53 %

Procedure:
The pure allyl 2,2-dinitroethyl ether, prepared according to the procedure set forth in Example 1, was added (4.11 grams; 0.0234 mole) slowly to a well stirred solution of sodium hydroxide (0.935 grams; 0.0234 mole), water (15 mls) and methanol (34 mls). The slightly exothermic reaction yielded an immediate orange color. The final pH was approximately 8. Perchloryl fluoride was then metered into the system to which was added a dry ice reflux condenser to prevent excess perchloryl fluoride from sweeping out of the reaction flask. When the perchloryl fluoride began to reflux vigorously, it was shut off and under slight nitrogen flow reflux was maintained for about 4 hours. The reaction temperature was maintained between 20°-25° C. with a water bath. The reaction mixture changed from deep orange to pale orange in color. Water (50 mls) was added and a yellow oil dropped out of solution. The mixture was then extracted with three 60 ml portions of methylene chloride. The methylene chloride extracts were washed with three 30 ml portions of 3 percent sodium hydroxide and finally with water. After drying with magnesium sulfate, excess methylene chloride was removed under vacuum and the residual liquid was distilled through a small Vigreux column. The distillation yielded 2.4 grams (53% yield) of allyl 2,2-dinitro-2-fluoroethyl ether, b. p. 42° C./1.1 mm, nD25 1.4240, d25 1.28. The calculated elemental analysis for C5H7N2O5 was C, 30.93; H, 3.64; N, 14.43. The found analysis was C, 30.85; H, 3.45; N, 14.43. The infrared spectrum for the compound, in Nujol, exhibited maximum peaks at 6.2, 7.6 and 9.0 microns.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:17][C:18]([O:20]C)=O)[CH2:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:20]=[C:18]1[CH2:17][CH:4]2[CH2:5][N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]3[C:3]2=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1]1
Reactant: CCOC(=O)CN1CC(CC(=O)OC)c2c(N)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1CC2CC(=O)Nc3cccc1c32
Temperature: 25 °C

Procedure:
To a solution of (±)-ethyl methyl 2,2′-(4-amino-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step D (490 mg, 1.70 mmol) in toluene (35 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) and the mixture was heated at reflux for 48 h. The mixture was cooled to ambient temperature and was partitioned between saturated aqueous NaHCO3 (5 mL) and EtOAc (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—90:10 to 40:60, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralpak AS column and eluting with MeOH. The first major peak to elute was ethyl (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer A, and the second major peak to elute was ethyl (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2B)-yl)acetate, enantiomer B, the title compound. MS: m/z=261 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12]Br.Br>C(O)(=O)C.O>[Br:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1Br

Procedure:
5-Chloroindan-1-one is reacted with bromine in glacial acetic acid using a catalytic amount of 48% strength HBr solution in water at room temperature. 2-Bromo-5-chloroindan-1-one is obtained with a melting point of 94-96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:5]([S:7]([NH:10]C(OCC1C=CC=CC=1)=O)(=[O:9])=[O:8])[CH3:6]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[N:5]([S:7]([NH2:10])(=[O:8])=[O:9])[CH3:6]
Reactant: COC(=O)C(CCC(C)C)N(C)S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CCC(C)C)N(C)S(N)(=O)=O
Reaction time: 3.5 h
Yield: 98.7 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (20.6 g, 53.17 mmol) in 200 ml of methanol under nitrogen was cooled to 0° C. and 1.5 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 3.5 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo to afford 13.24 g (98.6%) of N-(aminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:21][CH2:20][C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:37])C=1Cl>C1COCC1.O>[CH2:25]([O:24][C:22]([C:10]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[C:20](=[O:37])[CH2:21][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH:9]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (190 mg, 0.5 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (139 mg, 0.6 mmol) was added a mixture of THF-H2O (9:1, 8 mL) at ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 2 hours. Additional DDQ (139 mg, 0.6 mmol) was added, and the mixture was stirred at ambient temperature for another 2 hours. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed thoroughly with saturated sodium bicarbonate solution and then with brine. The organic phase was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (85:15) to give the title compound as a yellow solid (180 mg, 92%); 1H-NMR (CDCl3): δ 11.4 (1H, s), 8.52-8.48 (2H, m), 7.66-7.62 (2H, m), 7.48-7.46 (1H, m), 7.37-7.31 (2H, m), 7.22-7.17 (2H, m), 4.53 (2H, s), 4.38 (2H, q), 1.35 (3H, t); MS (ES): 393 (MH+).
Reaction SMILES: C([O:5][C:6]([C:8](NC(=O)OC(C)(C)C)=[CH:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.Cl.[O:28]1CCOCC1>>[C:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH:9]=[C:8]([OH:28])[C:6]([OH:5])=[O:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Yield: 76 %

Procedure:
The compound from Example 5 (6.0 g, 16.3 mmol) was treated with 4N HCl-dioxane (64 mL) for 1 h at room temperature. After removal of the solvent, the residue was dissolved in AcOEt, washed with 5% citric acid and saturated NaCl, dried over Na2SO4, and concentrated in vacuo to obtain 2.6 g (76%) of the title compound as a white solid: mp 153-155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 6.55 (s, 1H), 1.36 (s, 1H); m/z 211.0841 (M+) (calcd for C10H13NO4: 211.0844).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:20])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[Cl:19])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCOC(C)=O.O>C(O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:8]2[CH:9]=[C:4]([N:1]3[CH:24]=[C:23]([CH2:22][CH2:21][OH:25])[N:3]=[N:2]3)[CH:5]=[CH:6][C:7]=2[CH3:20])=[O:11])=[C:13]([Cl:19])[CH:14]=1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: C#CCCO
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound 470 (1.04 g, 2.97 mmol) in ethanol (18 mL) was added but-3-yn-1-ol (225 μL, 2.97 mmol), copper(II) sulphate pentahydrate (30 mg, 0.12 mmol) and a solution of sodium ascorbate (119 mg, 0.6 mmol) in water (3.0 mL). The flask was closed and stirred for 24 h at RT under argon. After 18 h was added but-3-yn-1-ol (225 μL, 2.97 mmol), copper(II) sulphate pentahydrate (30 mg, 0.12 mmol) and a solution of sodium ascorbate (119 mg, 0.6 mmol) in water (3.0 mL). After 2 h the reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 3:1 as the eluent to afford the title compound as offwhite solid.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:3][C:4]=2[O:16][CH3:17])[N:8]=1
Reactant: COc1cc(Cl)ccc1Oc1cccc(F)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2ccc(C)cc2)ccc1Oc1cccc(F)n1
Temperature: 105 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine (0.53 mmol; 135 mg) and 4-methylphenylboronic acid (0.94 mmol; 127 mg) in a degased DME/water mixture (1.5/0.5 mL), under argon were added K2CO3 (2.0 mmol; 276 mg), then tetrakis(triphenylphosphine)palladium (0.07 mmol; 47 mg). The reaction was stirred at 105° C. for 48 hr. After concentration, the residue was purified by flash chromatography (gradient cyclohexane/dichloromethane) to yield the desired product along with remaining starting material (160 mg; 0.53 mmol; 100% max).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.[OH-].[Na+].OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.[Cl-].[Na+]>O>[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.[NH2:5][C@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[CH:3]=[O:2]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C(O)c1cccnc1
Agent: [Cl-]
Solvent: O
Product: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
10.7 g (0.05 moles) of glucosamine hydrochloride are dissolved in 52 ml of water. 6.3 g (0.051 moles) of nicotinic acid are suspended in 20 ml of water containing one drop of alcohol, and a solution of 2 g (0.05 moles) of sodium hydroxide in 10 ml of water is added dropwise to the suspension, whereupon nicotinic acid dissolves. The resulting solution is admixed with the aqueous solution of glucosamine hydrochloride. 100 g of a slightly yellowish solution are obtained, which contains 15 g of the nicotinic acid salt of glucosamine (equivalent to 6 g of nicotinic acid) and 3 g of sodium chloride. The optical rotation power of the resulting solution is [α]D =+35.8°.