Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1>Cl>[Br:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Br)cn1
Agent: Cl
Product: Nc1cc(NCC2CCNCC2)c(Br)cn1
Temperature: 105 °C
Yield: 92.2 %

Procedure:
A mixture of benzyl 4-((5-bromo-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.695 g, 1.24 mmol) and 6M HCl (10 mL) was heated at 105° C. for 45 mins by microwave irradiation. After cooling the volatiles were removed in vacuo. The residue was redissolved in MeOH and adsorbed onto (solute SCX-II acidic resin. The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated to give crude 5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 92%), LCMS (4) Rt=0.51 min; m/z (ESI+) 285/287 (MH+). A solution of di-tert-butyl dicarbonate (0.249 g, 1 eq.) in dichloromethane (1 mL) was added dropwise to an ice-cooled solution of 5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 1.14 mmol) and triethylamine (0.48 mL, 3 eq.) in dichloromethane (7.79 mL). The solution was stirred at 0° C. for 30 mis and then warmed to room temperature and stirred for a further 30 min. The mixture was concentrated. The crude product was purified by preparative TLC, eluting with 7% MeOH, 1% NH3, 92% dichloromethane, to give tert-butyl 4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate (234 mg, 53%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([OH:24])([CH3:22])[CH3:23])[N:20]=2)[CH:7]=1
Reactant: CC(C)(O)c1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)O)n1
Temperature: 130 °C
Yield: 59 %

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (0.45 g, 2.04 mmol) and 2-(6-aminopyridin-2-yl)propan-2-ol (620 mg, 4.07 mmol) was dissolved in acetonitrile (3.00 mL) and heated at 130° C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 μM, 160 g, Thomson) eluting with 0 to 100% hexanes/ethyl acetate over 40 min, to yield ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (405 mg, 59.1% yield). 1H NMR (CHLOROFORM-d) δ: 10.72 (s, 1H), 9.00 (s, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 5.21 (br. s., 1H), 4.60 (q, J=7.2 Hz, 2H), 1.67 (s, 6H), 1.54 (t, J=7.9 Hz, 3H); LC-MS 337.0, 339.0 [M+H]+.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.Cl.[CH3:14][NH:15][CH:16]([CH3:25])[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>O>[CH3:25][C@H:16]([NH:15][CH3:14])[C@@H:17]([OH:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CNC(C)C(=O)c1ccccc1
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Reaction time: 48 h

Procedure:
Mycobacterium smegmatis IAM-12065 was inoculated to a medium containing 1% glucose, 0.5% peptone, and 0.3% yeast extract, and shake-culturing was aerobically carried out at 30° C. for 48 hours. After the cultured solution (1 l) was centrifuged to give bacterial cells, the cells was suspended in 50 ml of water, and after addition of dl-2-methylamino-1-phenyl-1-propanone hydrochloride (0.5 g), reciprocation-shaking was carried out at 30° C. and at 150 rpm. One hundred hours after the start of shaking, 7.0 g/l of d-pseudoephedrine was produced in the reaction solution. After the reaction solution was centrifuged to remove the bacterial cells, the pH was adjusted to 12 or greater by addition of sodium hydroxide. Methylene chloride (100 ml) was added to this reaction solution and the reaction product was extracted. The solvent was removed, hydrochloric acid was added, and then concentration to dryness yielded a hydrochloride salt. The hydrochloride salt was dissolved by addition of ethanol and further addition of ether crystallized the reaction product. Consequently, d-pseudoephedrine hydrochloride was obtained. The resulting d-pseudoephedrine crystals (0.32 g) were analyzed on HPLC (Column Sumichiral AGP manufactured by Sumika Chemical Analysis Service; diameter of 4 mm; length of 150 mm; 0.03 M sodium phosphate buffer; pH 7.0; flow rate of 0.5 ml/min; detection light wavelength at UV 220 nm) and the optical activity was found to be 100%.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[S:11](=O)(=[O:14])([OH:13])[OH:12].C1(S(O)(=O)=O)C2C(=CC=CC=2)C=CC=1.C(O)(=O)C1C(=CC=CC=1)C(O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])=O.[Na+].[Na+]>O>[OH:9][C:1]([C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:8]=1)[S:11]([OH:14])(=[O:13])=[O:12])[OH:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1ccccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)c1ccccc1C(=O)O
Agent: O=S(=O)(O)c1cccc2ccccc12
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 gms of naphthalene and 25 ml of conc. sulfuric acid were taken into a 250 ml round bottomed flask fitted with a stirrer. The contents of the flask were heated to 80° C. for 120 minutes with constant stirring. A drop of the resulting mass was taken in a beaker and 1 ml water was added to the same with shaking. A clear solution without any naphthalene smell was obtained confirming the completion of sulfonation. Simultaneously, 0.5 gm salicylic acid was taken in a separate beaker and 0.5 ml concentrated sulfuric acid was added with stirring at 25° C. The slurry was left aside with occasional stirring for 3 hrs. The naphthalene sulfonic acid, prepared in flask was allowed to cool down to 60° C. and transferred a reactor fitted with a thermometer, stirrer and a dropping funnel. The mass was stirred continuously for a period of 10 min. while maintaining the temperature at 60° C. with the help of the thermostat. A mixture of 0.2 gm poly acrylic acid, 0.25 gm phthalic acid, 1 gm citric acid and 0.14 gm salicylic acid was dissolved in 10 ml water in a beaker and the same was added to the reaction mass in the reactor through the dropping funnel. The mixture was heated at 65° C. for 20 min. 250 gm of aluminium sulfate was added to the above mass along with 100 ml of water with vigorous stirring. The temperature of the bath was gradually raised to 70° C. and allowed heating to continue for another 60 min. The sulfo salicylic acid which was prepared in the beaker was added to above mass and heating was continued for another 30 minutes. The mixture was transferred to a bucket and pH was raised to 2.5 by adding 60 gms sodium sulfite dissolved in 100 ml water while continuing stirring. The air was passed through the resulting solution for a period of 70 minutes. Slurry was filtered using muslin cloth of pore size 5–10μ. The filtrate was drum dried at 130° C. and the powder stored in a plastic container.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[C:10]([CH:20]=[CH2:21])=[N:9]2)=[N:3]1>CCO.[OH-].[OH-].[Pd+2]>[CH2:20]([C:10]1[C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][C:16]=2[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[N:9]=1)[CH3:21]
Reactant: C=Cc1nn(Cc2ccn(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2ccn(C)n2)c2cccc(N)c12
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To 1-((1-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (2.36 g, 8.33 mmol) in EtOH (80 mL) was cautiously added palladium hydroxide on carbon (1.5 g, 20% wt). The reaction mixture was purged with nitrogen and hydrogen three times each. The mixture was agitated under H2 (45 psi) for 3 hours. The system was evacuated and purged with nitrogen. The mixture was filtered through Celite® and the filter pad was washed with MeOH/DCM (10:1, 300 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/hexanes 2:1) to provide the product (1.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]4[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=4[Cl:1])[N:10]=3)[CH2:12][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: Clc1ccccc1Oc1cccc(N2CCNCC2)n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4ccccc4Cl)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(2-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]([CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:6].C([O:19][C:20](=O)[CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)C>C1(C)C=CC=CC=1.ClCCCl>[CH2:15]([N:7]([CH2:5][CH3:6])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:20](=[O:19])[CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH3:16]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CCOC(=O)C(c1ccccc1)c1ccncc1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(NC(=O)C(c2ccccc2)c2ccncc2)cc1
Temperature: 60 °C
Yield: 32.7 %

Procedure:
Trimethylaluminum (2.0 mL of a 2.0 M solution in toluene, 4.0 mmol, 3.0 equiv) was added to a solution of N,N-diethyl-1,4-phenylenediamine (0.68 mL, 4.0 mmol, 3.0 equiv) in 1,2-dichloroethane (10 mL). The resultant solution was stirred at 23° C. for 30 minutes, and then phenyl-pyridin-4-yl-acetic acid ethyl ester (330 mg, 1.36 mmol, 1.0 equiv) was added. The reaction mixture was heated to 60° C. for 19 hours, cooled to 23° C., and quenched with 1 N aqueous tartaric acid. The pH of the reaction mixture was adjusted to 5, and the reaction mixture was extracted with three portions of ethyl acetate (50 mL). The combined organic extracts were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography (20% THF/hexanes grading to 100% THF) provided N-(4-Diethylamino-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide (160 mg). MS: 360 (M+1)
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].CC([O-])=O.[Na+]>C(O)C>[OH:14][N:13]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 4-chromanone (5 g, 33.7 mmol), hydroxylamine hydrochloride (2.34 g, 33.7 mmol and NaOAc (2.766 g, 33.7 mmol) in 100 mL of ethanol was refluxed for 18 h. After cooling to RT, the solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was dried (MgSO4), and the solvent was removed. The solid obtained was triturated with hexane and filtered to provide 4.1 g of 4-hydroxyiminochroman.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:44]([O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:44]([O:51][C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:57][CH:58]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of pyridine-2-carboxylic acid (2.0 g, 8.48 mmol) in N,N-dimethylformamide (DMF) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (3.5 g, 9.33 mmol) and N,N-diisopropylethylamine (DIEA) (0.742 mL, 32.7 mmol) and stirred at room temperature for 10 min. 4-Benzyloxyaniline hydrochloride (2.0 g, 8.48 mmol) was added to the solution, and stirring was continued for an additional 30 min. The solution was poured into a saturated aqueous solution of sodium bicarbonate on ice. Mechanically mixing the gummy residue in the bottom of the flask caused it to solidify. The product was collected by filtration, washed with water and dried to give a beige solid, 2.46 g (95%), which was used without further purification in the subsequent reaction. MS m/z 305 (MH+). 1H NMR(CDCl3) δ 5.07 (s, 2H), 7.0 (d, 2H), 7.30-7.50 (m, 6H), 7.70 (d, 2H), 7.92 (t, 1H), 8.32 (d, 1H) and 8.58 (d, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH2:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:11])=[O:10].C(OC(C)C)(C)C>C(O)=O>[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH:20][CH:1]=[O:3])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:10])=[O:11]
Reactant: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1NC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (184 ml) and formic acid (93 ml) was stirred for 30 minutes at room temperature. The mixture was cooled at 5° C. with ice-bath and added to 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270 g). The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was evaporated to give crystals. To the crystals was added diisopropyl ether and the mixture was stirred for 1 hour. The crystals were collected by filtration to give 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-formamidopyrazole (291.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)ncn1
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CCOCC2)ncn1
Temperature: 25 °C

Procedure:
53.0 g (2.7 mmol) 4-(6-chloropyrimidin-4-yl)morpholine are initially introduced into 260 ml ethanol. 132.9 g (2.7 mol) hydrazine hydrate are added and the mixture is stirred under reflux for 16 h. Thereafter, it is cooled to RT and approx. half of the solvent is removed by distillation. The mixture is cooled to 0° C. and the solid formed is filtered off It is rinsed with cold ethanol and the solid is dried first in air and then in vacuo.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:18][CH2:17]2)[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:13]1[C@@H:14]([CH:16]2[CH2:17][CH2:18]2)[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1C1CC1

Procedure:
A 10% palladium carbon catalyst (50 mg) was added to a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-cyclopropylpyrrolidine (408 mg, 1.13 mmol) in ethanol (5 mL), followed by stirring in a hydrogen atmosphere under an ordinary pressure at 45° C. for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (255 mg, quantitative amount). The product was employed, without further purification, in the subsequent step.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH:5]([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.N>>[Cl:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:3](=[O:2])[NH:4][CH:5]([CH3:14])[CH2:6]2
Reactant: COC(=O)NC(C)Cc1cccc(Cl)c1
Agent: N
Product: CC1Cc2cc(Cl)ccc2C(=O)N1
Temperature: 120 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-1-methyl-ethyl]-carbamic acid methyl ester (1.2 g, 5.3 mmol) and PPA (polyphosphoric acid) (10 g) in a 100 mL round bottom flask was stirred at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. The mixture was then extracted with ethyl acetate and the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product obtained was further washed with ether to give 6-chloro-3-methyl-3,4-dihydro-2H-isoquinolin-1-one (0.27 g, 26%) (intermediate A-3-1) as a white solid. MS: 196.1 (M+H+). The ether filtrate was concentrated under reduced pressure and purified by flash chromatography to afford 8-chloro-3-methyl-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-3-2) (54 mg, 5.2%) as a white solid. MS: 196.1 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNCCn1cnc(-c2cc(C(=O)O)ccn2)c1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-methoxybenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.91 (2H, t, J=5.9 Hz), 3.72 (2H, s), 3.75 (3H, s), 4.13 (2H, t, J=6.0 Hz), 6.88 (1H, t, J=7.4 Hz), 6.95 (1H, d, J=8.2 Hz), 7.20 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=7.4 Hz), 7.56 (1H, dd, J=6.4 and 1.4 Hz), 7.75 (1H, s), 7.82 (1H, s), 8.28 (1H, s), 8.59 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H20N4O3, 353. Found, 353.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:19]3[C:30](=[O:40])[N:31](C(OC(C)(C)C)=O)[CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:19]3[C:30](=[O:40])[NH:31][CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CNC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (58.9 mg, 0.100 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL, 8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and then concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (26.5 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.82-0.92 (m, 2H), 0.95-1.06 (m, 2H), 1.70-1.85 (m, 1H), 2.07-2.17 (m, 1H), 2.18-2.26 (m, 1H), 3.56-3.66 (m, 1H), 3.72-3.84 (m, 2H), 3.95-4.08 (m, 2H), 4.26-4.36 (m, 1H), 4.41-4.53 (m, 2H), 7.46 (d, J=4.88 Hz, 1H), 8.02 (br s, 3H), 8.68 (s, 1H), 8.72 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C18H20FN5O2S, 390. found, 390.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([OH:32])[CH2:5]2.[H-].[Na+].I[CH2:36][CH3:37]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:36][CH3:37])[CH2:5]2
Reactant: CCI
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H]1c2ccc(Br)cc2C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 4-{(3S)-4-[(1R,2R)-5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (564 mg, 1.1 mmol) in tetrahydrofuran (20.00 mL) was added sodium hydride (448 mg, 17.75 mmol) at room temperature. After stirring for 10 min, iodoethane (1.42 mL, 17.75 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous ammonium chloride solution (20 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude product (488 mg, 82%). LC-MS [M+1]=536.3, 538.8.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26].[OH-].[Na+]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17])(=[O:26])=[O:24]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(OS(=O)(=O)C(F)(F)F)ccc2c(C(F)(F)F)noc12
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (500 mg, 2.04 mmol) in dry CH2Cl2 was added pyridine (0.82 mL, 10.2 mmol) at 0° C. under N2. Tf2O was then added dropwise to the reaction mixture and the resulting mixture stirred for 30 min. 1N NaOH was added and the mixture extracted with CH2Cl2. Combined organic extracts were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate and hexane (10:90) to give the title compound.