Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([CH2:32][N+:33]#[C-:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(OCC)C>[N+:33]([C:32]([S:29]([C:26]1[CH:25]=[CH:24][C:23]([CH3:35])=[CH:28][CH:27]=1)(=[O:30])=[O:31])([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[C-:34]
Reactant: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [C-]#[N+]C(CCCCC(C)(COC1CCCCO1)c1ccc(C)cc1)(CCCCC(C)(COC1CCCCO1)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 2-(6-bromo-2-methyl-2-p-tolyl-hexyloxy)-tetrahydropyran (21.5 g, 58.27 mmol), tetra-n-butylammonium iodide (2.36 g, 6.41 mmol), and p-toluenesulphonyl-methyl isocyanide (TosMIC, 5.68 g, 29.14 mmol) in anhydrous DMSO (300 mL) and anhydrous diethyl ether (100 mL) was added sodium hydride (60% dispersion in mineral oil, 2.94 g, 73.42 mmol) at rt under N2 atmosphere. The mixture was stirred for 24 h at rt. The reaction mixture was carefully hydrolized with ice-water (500 mL) and extracted with diethyl ether (2×300 mL). The organic layer was washed with brine (2×300 mL), dried over anhydrous MgSO4, and concentrated in vacuo to furnish crude 2-[7-isocyano-2,12-dimethyl-2,12-di-p-tolyl-13-(tetrahydropyran-2-yloxy)-7-(toluene-4-sulfonyl)-tridecanyloxy]-tetrahydropyran (18.44 g) as a brown oil. A solution of this crude intermediate (18 g) in methanol (300 mL), concd. HCl (36 mL), and water (70 mL) was heated to reflux for 3 h. The reaction mixture was poured into CH2Cl2 (250 mL) and ice-water (250 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×100 mL) and brine (150 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (silica gel, ethyl acetate/hexanes=20/1, 15/1, 10/1, 5/1, and 1/1) to furnish 1,13-dihydroxy-2,12-dimethyl-2,12-di-p-tolyl-tridecan-7-one (2.72 g, 26.2% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.18 (d, 4H, J=8.1 Hz), 7.12 (d, 4H, J=8.1 Hz), 3.63 (d, J=11.0 Hz, 2H), 3.49 (d, J=1.0 Hz, 2H), 2.31 (s, 6H), 2.26 (t, J=7.8 Hz, 4H), 1.78-1.40 (m, 10H), 1.28 (s, 6H), 1.24-0.82 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 211.51, 141.75, 135.64, 129.23, 126.64, 72.54, 43.06, 42.65, 38.28, 24.53, 23.59, 21.66, 20.98. HRMS (LSIMS, nba): Calcd. for C29H43O3 (MH+): 439.3212, found: 439.3222.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:35]([CH:36]=O)=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1>CO.N1CCCCC1>[Br:26][C:27]1[CH:28]=[C:29]2[C:35](/[CH:36]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncc(Br)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (1.0 mL) was added with 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.044 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was suspended in methylene chloride and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.018 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O1CCOCC1.C(N(CC)CC)C>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:22][CH2:21][C:17]1[N:16]=[C:15]2[CH2:14][O:13][C:12](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:20]2=[CH:19][CH:18]=1)[CH3:24]
Reactant: CCNCC
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCN(CC)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Yield: 17.7 %

Procedure:
A solution of 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (60 mg, 0.20 mmol) and diethylamine (250 mg, 3.42 mmol) are reacted in a sealed tube at 100° C. for 2 h. The reaction vessel is cooled and additional diethylamine (250 mg, 3.42 mmol) in dioxane (10 mL) is added. The reaction vessel is sealed and heated at 100° C. overnight. The reaction mixture is cooled and treated with triethylamine (15 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated to provide the title compound (13 mg, 18%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:9][C:8]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(OC(=O)c2ccc(-c3ccccc3)cc2)cc1O

Procedure:
A solution of 2,4-dihydroxy benzoic acid tert-butyl ester (420 mg; 2 mmol), triethylamine (202 mg; 2 mmol) and p-phenyl benzoyl chloride (415 mg; 1.9 mmol) in dry CH2Cl2 was stirred under argon atmosphere at room temperature overnight after which time H2O was added. The organic phase was isolated, dried, evaporated to dryness and re-crystallized from 2-propanol to yield 195 mg (25%). MS (LC-MS): 389 (MH−).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:32][CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:33]C)[CH:29]=5)[C:24]4=[O:35])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.Br>>[CH2:13]1[C@@:10]2([CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH2:15][N:14]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=3)[C:24]2=[O:35])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc1)C2=O
Agent: Br
Product: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCNC3)C2)cc1

Procedure:
According to Method L, (S)-7-[4-(6-methoxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was treated with hydrogen bromide. In this way the product was obtained with molecular weight 363.46 (C22H25N3O2); MS (ESI): 364 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Br.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:15][CH2:14]1
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Reactant: COc1ccc(CBr)cc1OC
Product: COc1ccc(CN2CCC(c3ccc(-c4cccc(N)n4)cc3)CC2)cc1OC

Procedure:
Prepared from Example 13, using 3,4-dimethoxybenzyl bromide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 89%, mp 150-165° C. as the hydrochloride salt.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:26])=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=3[C@@:15]32[CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1)=[N+]=[N-].CP(C)C>C1COCC1.O>[F:26][C:10]1[C:9]2[O:8][C:7]3[C:16](=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=3)[C@@:15]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:14]=2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (290 mg, 0.816 mmol) in THF (3 ml) and water (1 ml) was added trimethylphosphine (1M in THF) (0.98 ml, 0.98 mmol) and the mixture was stirred at RT for 2 hrs. THF was removed under reduced pressure, water (5 ml) was added and the mixture was extracted with EtOAc. Organic extracts were washed with brine, dried with MgSO4 and concentrated. Recrystallization of the residue from DCM afforded (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (102 mg, 0.310 mmol, 38% yield).
Reaction SMILES: N[C@H](C(OC)=O)[C@H](CC)C.CC(C)(OC([NH:17][C@@H:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:19]([OH:37])[CH2:20][N:21]([CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][C@H:25]([C:30]([O:32][CH3:33])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])=O)C>Cl.O1CCOCC1>[NH2:17][C@@H:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[CH:19]([OH:37])[CH2:20][N:21]([CH:34]([CH3:35])[CH3:36])[C:22]([NH:24][C@H:25]([C:30]([O:32][CH3:33])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23]
Reactant: CC[C@H](C)[C@H](NC(=O)N(CC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C)C(=O)OC
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)N(CC(O)[C@@H](N)CC(C)C)C(C)C)C(=O)OC

Procedure:
The L-isoleucine, methyl ester, isomer A product from part (a) (0.25 g., 0.544 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 2.25 ml.). After keeping the solution at room temperature for 4 hours, it is evaporated in vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[N:13]([N+:21]([O-:23])=[O:22])C(OC(C)(C)C)=O)[CH2:7][CH2:8][O:9][CH3:10])[CH3:2].[ClH:33].C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH:13][N+:21]([O-:23])=[O:22])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 29.8 g of NG -nitro-N2 -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0° C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give 24.1 g of NG -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(C)n1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 76%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]([CH2:10][CH2:11][C:12](O)=[O:13])([CH3:9])[C:6]([OH:8])=[O:7]>S(=O)(=O)(O)O>[CH3:9][C:5]1([C:6]([OH:8])=[O:7])[C:4]2[C:15](=[CH:16][C:17]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:2]([Cl:1])[CH:3]=2)[C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CC(CCC(=O)O)(C(=O)O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CC1(C(=O)O)CCC(=O)c2cc(C3CCCCC3)c(Cl)cc21
Yield: 89.3 %

Procedure:
With thorough cooling 13.6 g of 3-chloro-4-cyclohexyl-α-(2-carboxyethyl)-hydratropic acid are dissolved in 70 ml of 100% sulfuric acid and the solution is kept over-night at room temperature, then cautiously poured out over ice and the aqueous mixture is extracted with ethyl acetate and the extract is evaporated. The resulting crystals are recrystallized from acetone, to yield 11.5 g of 1-methyl-4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, melting at 227°-228°C, of the formula ##SPC5##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: CO
Product: COC(=O)c1cc(I)ccc1Cl

Procedure:
A solution of 2-chloro-5-iodo-benzoic acid (25.63 g, 90 mmol) in methanol (500 mL) saturated with HCL gas was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo, diluted with 1:1 ethyl acetate/Diethyl ether and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (25.0 g).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:2].[CH2:15]([B-](F)(F)F)/[CH:16]=[CH:17]\[CH3:18].[K+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:2][C@@H:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:17]([CH3:18])[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C/C=C\C[B-](F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=C[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 13 h
Yield: 101.8 %

Procedure:
To a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (10 g, 50 mmol, 1 eq.) in dichloromethane (120 mL, 0.42 M) was added potassium (2Z)-2-buten-1-yltrifluoroborate (9.76 g, 60.2 mmol, 1.2 eq.) followed by tetra-n-butylammonium bromide (3.24 g, 5.02 mmol, 0.1 eq.) and water (60 mL). After 13 hours, the reaction was diluted with dichloromethane (150 mL) and water (150 mL). The aqueous layer was separated and back-extracted with dichloromethane (100 mL). The combined organic layers were washed with aqueous sodium chloride solution (5% wt, 200 mL), washed with water (200 mL), and concentrated in vacuo to afford #9 (˜13 g) as an orange oil, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 5.61-5.86 (br m, 1H), 4.97-5.09 (m, 2H), 3.80-3.98 (br m, 2H), 3.45-3.67 (br m, 1H), 3.21-3.29 (m, 1H), 2.14-2.26 (m, 1H), 1.80-2.04 (m, 3H), 1.65-1.76 (m, 1H), 1.47 (s, 9H), 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:6]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccccc1F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 2-Amino-5-bromo-nicotinic acid (1 g, 4.61 mmol) and SOCl2 (5 mL) in toluene (15 mL) was stirred at 130° C. for 2 h. After concentrated, the residue was dissolved in tetrahydrofuran (20 mL), and then 2-fluoro-phenylamine (1.09 g, 9.81 mmol) was added dropwise at 0° C. The reaction mixture was heated to 90° C. for 4 h. After being cooled to room temperature and quenched with saturated aqueous K2 CO3 (10 mL), the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=2:1) to give 2-amino-5-bromo-N-(2-fluorophenyl)nicotinamide (1.0 g, 70% yield) as yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.25˜8.28 (m, 2H), 7.86 (d, J=2.4 Hz, 2H), 7.13˜7.22 (m, 3H), 6.36 (s, 2H). MS (M+H)+: 311/313.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2].CC(C)=[O:29]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:8][C:9](=[O:29])[CH3:26])[C:12]([C:11](=[O:10])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:14]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: COc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)c(CC(C)=O)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of compound 14 (0.375 g, 1.05 mmol) in 30 ml of acetone was added 3 ml of CrO3 in 35% H2SO4 at 0° C. The resulted solution was stirred another 2 h at same temperature. Ice water was added. The solution was extracted with ethyl acetate three times. The combined organic phase was washed with brine, followed by drying over Na2SO4. Removal of the solvent afforded the desired product in the yield of 82%. 1HNMR(CDCl3): 8.5-7.8 (m, 6H), 6.8 (s, 1H), 4.08 (s, 2H), 3.8 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
22 g (75 mmol) of 1,4-dibenzyl-2-aminomethylpiperazine dissolved in 300 ml of toluene are mixed with 100 ml of triethylamine in a ground-necked conical flask. 97 ml (0.1 mol) of isopropyl chloroformate, taken up by syringe, are dissolved in 50 ml of toluene, and are then added dropwise to the above solution. At the end of the addition, the mixture is stirred for 2 hours at room temperature. The solution is diluted with ether, washed with saturated NaHCO3 solution and then with water to obtain a neutral pH. The organic phase is dried (MgSO4), filtered and evaporated to give 28.3 g of 1,4-dibenzyl-2-isopropyloxycarbonylaminomethylpiperazine in the form of a viscous compound. Yield: 99.6%. Rf=0.4 (95/5 v/v CH2Cl2/MeOH).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=2)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:39][C:40]([CH3:42])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:2]([O:4][C:5]([C:7]1[N:8]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:23])=[O:24])[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]1[CH2:21][CH2:20][N:19]([CH:40]([CH3:42])[CH3:39])[CH2:18][CH2:17]1)=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2cc(C3CCNCC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(C3CCN(C(C)C)CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A mixture of 5-piperidin-4-yl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester hydrochloride (253 mg, 0.592 mmol) in dichloroethane (4 ml), triethylamine (0.17 ml, 1.18 mmol), acetone (1.44 ml, 19.6 mmol), acetic acid (0.28 ml, 4.89 mmol), and sodium triacetoxyborohydride (318 mg, 1.50 mmol) was stirred at room temperature for 14.5 hours. The pH of the reaction mixture was adjusted to 9 (basic) using an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. The resulting residue was purified by amino gel column chromatography (hexane/ethyl acetate=92/8 to 35/65). Thus, 5-(1-isopropyl-piperidin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester was obtained as a colorless gum-like material (191 mg, 69%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](N(CC)CC)[CH3:11]>C(O)C.Cl>[CH3:10][CH2:11][O:8][C:7](=[O:9])[C@@H:2]([CH2:3][C:4]([OH:6])=[O:5])[NH2:1]
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](N)CC(=O)O
Reaction time: 2 h
Yield: 71 %

Procedure:
13.31 g of D-aspartic acid (0.1 mole) are dissolved in 135 ml of absolute ethanol containing 8.7 g of dry hydrogen chloride. The reaction mixture is stirred for about 2 hr. The solution is diluted by addition of 250 ml of absolute ethanol. Triethylamine is then added dropwise until the solution becomes alkaline. After standing for 16 hr at +4° C., the obtained crystals are filtered, washed successively with cold absolute ethanol and ether, then dried. The reaction yields 11.5 g of D-aspartic acid β-ethyl ester (71%).