Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>O1CCCC1>[O:10]=[C:9]([CH3:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:7][CH:6]=1
Reactant: CC(=O)Cc1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 1-(4-aminophenyl)acetone (1.13 g, 7.57 mmol) and pyridine (1.84 ml, 22.7 mmol) in tetrahydrofuran (50 ml) was added 2,2,2-trichloroethyl chloroformate (1.57 ml, 11.4 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling and then at room temperature for 1 hour, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (1.44 g, 58.4%) as an oil.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chlorooxoacetate (2.5 g, 20.7 mmol) was added dropwise to a mixture of tert-butyl trans-4-(4-aminophenyl)cyclohexanecarboxylate (3.8 g, 13.8 mmol) and pyridine (2.2 mL, 27.6 mmol) in DCM (40 mL) at 10° C. The reaction mixture was warmed to room temperature and stirred for 16 h and then quenched with water. The layers were separated and the organic layer was washed with brine. The organic layer was dried and concentrated in vacuo and the residue was purified by chromatography, eluting with 10-50% ethyl acetate in isohexane, to give the title compound (4.0 g, 80%) as an oil; 1H NMR δ 1.4 (9H, s), 1.4-1.55 (4H, m), 1.8-1.9 (2H, m), 1.9-2.05 (2H, m), 2.2-2.3 (1H, m), 2.4-2.6 (1H, m), 3.75 (3H, s), 7.2 (2H, d), 7.65 (2H, d); MS m/e (M−H)− 360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)(=[O:11])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(F)cc(Br)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(F)cc(Br)c1)c1ccc(O)cc1
Yield: 98.3 %

Procedure:
N-(3-Bromo-5-fluorophenyl)-4-methoxybenzenesulfonamide (507 mg, 1.41 mmol) was treated with boron tribromide (1M in dichloromethane, 7.0 ml, 7 mmol) using dichloromethane (10 ml) as a solvent according to the method described in Example 23. The resulting crude was purified by flash chromatography using SP1® Purification System (0% to 40%, dichloromethane-ethyl acetate) to obtain 480 mg (99% yield) of the title compound. Purity: 100%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].B(OB=O)=O.[OH:22][C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([CH:30]=1)[CH:28]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:16])[CH2:12][C:13](=[O:15])/[CH:14]=[CH:28]/[C:27]1[CH:30]=[C:23]([OH:22])[CH:24]=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)C=Cc1ccc(O)cc1Cl
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: CCCCN
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(O)cc1Cl)CC(=O)/C=C/c1cc(O)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 10.6 %

Procedure:
6-(2-Chloro-4-hydroxyphenyl)hex-5-ene-2,4-dione (20.3 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 5-hydroxy-2-nitrobenzaldehyde (18 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol), sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (3.5 mg, 7%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]2[CH2:20][CH2:21][CH2:22][C:23]2=[O:25])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: COC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCCC1=O)CCCN2
Reaction time: 1.5 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 5.0 g, 17.99 mmol), methyl 4-aminobutanoate hydrochloride (4.14 g, 27.0 mmol) and triethylamine (4.24 ml, 30.6 mmol) in 1,2-dichloroethane (85 ml) at room temperature was stirred for 1.5 h and sodium triacetoxyborohydride (5.72 g, 27.0 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and DCM, extracted 2× with DCM, dried over Na2SO4 and evaporated. The residue was triturated with Et2O (20 ml) and filtered washing with Et2O to give the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13](=[O:19])[NH:12][C:11]=2[N:10]=1)([CH3:7])[CH2:3][CH2:4][CH:5]=O.Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[O:8][C:9]2[N:10]=[C:11]3[C:16]([CH2:15][CH2:14][C:13](=[O:19])[NH:12]3)=[CH:17][CH:18]=2)[CH2:31][CH2:30]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC(C)(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
To a solution of 4-methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (335 mg, crude) in DCE (6 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (335 mg, 1.25 mmol) followed by Et3N (0.35 mL, 2.50 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (365 mg, 1.72 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (395 mg, 0.827 mmol, 67% over 2 steps). The foam was dissolved in Et2O and 1 N HCl in Et2O (0.85 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (386 mg). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O-:18])=[O:17])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(-c2ccccc2F)nc1C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Product: Nc1cc(F)c(-c2ccccc2F)nc1C(=O)O
Yield: 90 %

Procedure:
Method 2 was followed using 3-amino-5-fluoro-6-(2-fluorophenyl)picolinate (1.0 equiv.) and LiOH (5.0 equiv.) to give 3-amino-5-fluoro-6-(2-fluorophenyl)picolinic acid in 90% yield. LC/MS=251.1 (M+H), Rt=0.80 min.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:24]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:24])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester (38 mmol) and MeI (10 mL, 160 mmol) in 150 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 51 mL, 76.5 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous solution of NH4Cl (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried with anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10:1 to 5:1 hexane/ether to afford N-BOC-1-methyl-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42]>>[CH2:41]([N:43]([CH2:44][CH3:45])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([OH:32])=[CH:16][CH:17]=3)[O:12]2)=[CH:9][CH:10]=1)[CH3:42]
Reactant: CCNCC
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Product: CCN(CC)CCOc1ccc(C2Oc3cc(O)ccc3C(C)=C2c2cnc(OC)nc2OC)cc1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and diethyl amine as the starting material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([SH:17])([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([CH3:16])([S:17][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a CH3CN (50 mL) solution containing methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-mercapto-3-methylbutanoate (as described above) (1.26 g, 4.78 mmol, 1.0 eq) was added sodium tert-butoxide (597 mg, 6.21 mmol, 1.3 eq). The resulting pale yellow mixture was allowed to stir at RT for 10 min at which time (2-bromoethyl)benzene (718 μL, 5.26 mmol, 1.1 eq) was added. The resulting solution was allowed to stir at RT for 18 hr. The reaction was then quenched with a sat NH4Cl solution, poured into H2O, and extracted (2×) with EtOAc. Combined extracts were dried over MgSO4 and concentrated in vacuo. Purified via flash chromatography using 5:1 hexanes/EtOAc as the mobile phase. Isolated 761 mg (2.07 mmol, 45% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)C.Cl.[NH2:25][OH:26].C[O-].[Na+]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[OH:26][NH:25][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CCOC(=O)CCCCCn1c2ccccc2c2ccccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCCCCn1c2ccccc2c2ccccc21)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.2 %

Procedure:
6-Carbazol-9-ylhexanoic acid ethyl ester (14) (1.0 g, 3.2 mmol) and hydroxylamine hydrochloride (1.4 g, 19.4 mmol) were placed under argon and dissolved in 5 mL of methanol. To it was added a 25 wt. % sodium methoxide solution in methanol (5.6 g, 25.9 mmol) which resulted in the formation of a white precipitate. The reaction was stirred for 24 h at room temperature after which the reaction was diluted with ethyl acetate (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude extract was purified by HPLC to yield the title compound (0.41 g, 41%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.29 (s, 1H), 8.64 (s, 1H), 8.15 (d, 2H, J=7.7 Hz), 7.59 (d, 2H, J=8.2 Hz), 7.46 (m, 2H), 7.19 (m, 2H), 4.37 (t, 2H, J=7.1 Hz), 1.90 (t, 2H, J=7.3 Hz), 1.76 (m, 2H), 1.51 (m, 2H), 1.30 (m, 2H). 13C NMR (100 MHz, DMSO): δ 169.4, 140.4, 126.1, 122.4, 120.7, 119.1, 109.6, 42.6, 32.6, 28.7, 26.6, 25.3. ESI-HRMS (m/z): [M+H]+ calcd. for C18H20N2O2, 297.1598. found, 297.1591. Analytical HPLC: Purity=99%, tR=10.54 min, Method A.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38].[OH-].[Na+].O>CC(C)=O>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(O)c2)cc1
Reactant: ClCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
(3RS,4RS)-4-(3-Hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (260 mg, 0.59 mmol), 1-bromo-4-chlorobutane (0.8 ml, 2.98 mmol) and aqueous 2N-NaOH solution (0.8 ml) were dissolved in acetone (10 ml) and then stirred for 4 hours at 50° C. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 300 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1.[O:15]1[CH2:20][CH2:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH2:16]1>O1CCOCC1.CCOC(C)=O.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>[Cl:14][C:13]1[C:8]([C:17]2[CH2:16][O:15][CH2:20][CH2:19][CH:18]=2)=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1nccnc1C1=CCCOC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium carbonate (6.48 mL, 12.95 mmol, 2.0 M in water) was added to a stirred mixture of 2,3-dichloropyrazine (1.28 mL, 8.63 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.91 g, 4.32 mmol), and tetrakis(triphenylphosphine)palladium (0.50 g, 0.43 mmol) in dioxane (16 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 16 h before being cooled to room temperature and diluted with EtOAc. The mixture was washed with water, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine. [M+1]=197.0.
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([O:14]C)=[C:9]([CH3:16])[CH:8]=2)=[CH:4][C:3]=1[CH3:20].Br>C(O)(=O)C>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH3:16])[C:10]([OH:14])=[C:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: COc1c(C)cc(Oc2cc(C)c(Cl)c(C)c2)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(Oc2cc(C)c(Cl)c(C)c2)cc(C)c1O
Yield: 102.4 %

Procedure:
40 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-anisole were added to a solution of 125 ml of 48% hydrobromic acid and 300 ml of glacial acetic acid. The mixture was then refluxed for 2 hours at the reflux condenser. After concentration under reduced pressure, water was added to the residue and the mixture was extracted with methylene chloride. After the organic extract had been shaken several times with water, it was concentrated and the residue was distilled under greatly reduced pressure. 39 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-phenol were obtained, boiling point: 186°-190° C. under a pressure of 2-3 mm mercury.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH:17]12[O:22][CH:21]1[CH2:20][CH2:19][CH2:18]2>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C@@H:20]2[CH2:19][CH2:18][CH2:17][C@H:21]2[OH:22])[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=S(=O)(c1ccccc1Cl)N1CCNCC1
Reactant: C1CC2OC2C1
Solvent: CCO
Product: O=S(=O)(c1ccccc1Cl)N1CCN([C@@H]2CCC[C@H]2O)CC1
Temperature: 80 °C

Procedure:
1-(2-Chlorophenylsulfonyl)piperizine (1 eq, 0.19 mmol) was dissolved in ethyl alcohol (2 ml), then treated with 6-oxa-bicyclo[3,1,0]hexane (2eq, 0.38 mmol), the reaction solution was heated to 80° C. for 8 hour. The reaction mixture was purified by prep-HPLC. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.36-1.48 (m, 1 H), 1.49-1.74 (m, 3 H), 1.81-2.03 (m, 2 H), 2.52-2.67 (m, 3 H), 2.68-2.78 (m, 2 H), 3.28-3.37 (m, 4 H), 3.99-4.18 (m, 1 H), 7.33-7.42 (m, 1 H), 7.44-7.58 (m, 2 H), 7.98 (d, J=8.21, 1.14 Hz, 1 H); ESI-MS: m/z 345 (m+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>>[C:25]([O:24][C:22]([NH:21][CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: [Li+]
Agent: [OH-]
Product: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
A sample of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester was hydrolyzed with 2 eq of LiOH as described in Example 1D to give 1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid: 1H NMR (DMSO-d6) δ 1.37 (s, 9H), 3.90 (s, 3H), 3.93 (s, 3H), 4.74 (d, 2H), 7.33-7.36 (m, 1H), 7.61 (s, 1H), 8.37 (s, 1H), 8.82 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[H-].[Na+].Br[CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][N:8]1[C:7]2[C:15](=[CH:16][CH:17]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:28]
Reactant: CCCCC(CC)CBr
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To 11H-benzo[a]carbazole (0.70 g; 3.22 mmol) in DMF (3 ml) is added sodium hydride (0.19 g; 4.67 mmol) at 0° C., After stirring 1 h at 0° C., 1-bromo-2-ethylhexane (1.24 g; 6.44 mmol) is added at 0° C., and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with AcOEt (acetic acid ethyl ester). The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated and dried in vacuo to give a yellow liquid as a crude product (1.08 g). The product is used for the next reaction without further purification. The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.80-0.92 (m, 6H), 1.16-1.47 (m, 8H), 2.27 (m, 1H), 4.65-4.69 (m, 2H), 7.27 (td, 1H), 7.44-7.59 (m, 4H), 7.66 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[O:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[O:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of methyl 3-formylbenzoate (492 mg, 3.0 mmol) in MeOH (10 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (945 mg, 15.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated and the residue was dissolved in water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-TLC to give the title product (500 mg, Yield 67%). LCMS (m/z): 250.1 (M+1).