Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1)#[N:16]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)O
Temperature: 33 °C
Reaction time: 1 h

Procedure:
To the stirred solution of 5-cyano-3-methylpyridine-2-carboxylic acid tert-butyl ester (20.7 g, 94.9 mmol) in toluene (200 mL) was added H2O (3.4 mL) at ambient temperature. The mixture was then cooled to 0˜5° C. with stirring, at this point, TFA (200 mL) was added to the mixture slowly while maintaining the reaction temperature at 25˜35° C. The reaction mixture was then heated at 33° C. with stirring. After 60 min, to the reaction mixture was added toluene and the mixture was concentrated in vacuo to ˜¼ of the original volume to remove TFA by azeotropic distillation with toluene. To the concentrated mixture was added toluene and the mixture was evaporated in vacuo to ˜¼ of the original volume. The same evaporation manipulation was repeated once and the precipitated product was collected by filtration. The filter cake was washed with toluene and dried in vacuum oven at 50° C. for 8 h to give the title compound as a pale yellow crystalline solid: ESIMS: 163; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.35 (s, 1H), 2.46 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Reaction time: 16 h
Yield: 47 %

Procedure:
A mixture of 3-aminopyridine (2.60 g, 27.60 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.50 g, 27.60 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.57 mL, 1.66 g, 27.60 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (7.02 g, 33.12 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→4:1) to yield 3.60 g (47%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, CDCl3): δ 1.28-1.41 (m, 2H), 1.47 (s, 9H), 2.04 (dd, J=12.8 Hz, J=2.6 Hz, 2H), 2.93 (t, J=12.3 Hz, 2H), 3.44 (br s, 1H), 3.58 (br s, 1H), 4.07 (d, J=10.7 Hz, 2H), 6.83-6.91 (m, 1H), 7.08 (dd, J=8.2 Hz, J=4.5 Hz, 1H), 7.96 (d, J=3.6 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H). MS (ESI): 278.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (153 mg, 6.4 mmol) in portions. After the vigorous gas evolution stops, add 2-bromo-propane (0.60 mL, 6.4 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (300 mL) and extract with ethyl acetate (2×150 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with 5% ethyl acetate in hexanes to yield 1.1 g of 1-bromo-4-isopropylsulfanyl-benzene (92%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 40.2 %

Procedure:
A solution of 7′-bromo-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1H)-naphthalene] (3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml, 50 mmol) (Aldrich), triphenylphosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.25 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether: hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3′,4′-dihydro-7′[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2′(1′H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3), 1.93 (t, J=7 Hz, 2 CH2), 2.95 (t, J=7 Hz, 2H, CH2), 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][S-:17].[Na+]>C1COCC1>[CH3:16][S:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
To a stirred mixture of 2-bromobenzo[d]thiazole-6-carboxylate (2.3 g, 7.9 mmol) from Step 1 of this Example in THF (15 mL) at 0° C. was added sodium thiomethoxide (607 mg, 8.7 mmol) in one portion. The mixture was allowed to warm to rt and stirred for 20 h. The mixture was partitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layer was separated and washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate (1.7 g, 83%) as a yellow solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.3 Hz, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.83 (s, 3H), 1.35 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH:23]([CH3:25])[CH3:24])[C:14]=2[CH:26]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl>[Br:2][C:1]([Br:5])=[CH:26][C:14]1[C:15]([CH:23]([CH3:25])[CH3:24])=[N:16][C:17]2[C:22]([C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (12.620 gm, 38.0 mmol) in CH2 Cl2 (20 ml) was added over a 10 minute period to a cold (-10° C.) solution of 4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (7.394 gm, 25.2 mmol) and triphenylphosphine (19.86 gm, 75.7 mmol) in CH2 Cl2 (140 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to 50 ml. The residue was triturated with Et2O and the precipitated triphenylphosphine oxide was removed by filtration. The filtrate was stripped and the residue was chromatographed (flash, Merck SiO2, 10% EtOAc in hexane) to give 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline as a light yellow foamy oil (11.556 gm, 102% theory).
Reaction SMILES: C(OCC)(=O)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 5 °C

Procedure:
To 300 ml of an ethyl acetate solution containing 30.00 g of N-t-butoxycarbonyl-4-hydroxypiperidine and 41.6 ml of triethylamine was added dropwise 17.3 ml of mesyl chloride at −10° C. over 10 minutes. The temperature increased to 5° C. due to heat generation. After stirring with cooling in an ice bath for 10 minutes, 90 ml of water was carefully added dropwise to the reaction mixture. The temperature increased from 0° C. to 6° C. due to heat generation. After stirring for 10 minutes, the mixture was separated and the organic phase washed with water (90 ml×2), saturated saline (90 ml), water (90 ml) and saturated saline (90 ml) in this order. After drying with anhydrous magnesium sulfate, concentration was conducted under reduced pressure and 40.74 g of 1-t-butoxycarbonyl-4-mesyloxypiperidine was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1

Procedure:
To a cooled (5-10° C.) mixture of N-Boc-4-hydroxypiperidine (25.0 g, 124 mmol) and triethylamine (19.6 ml, 136 mmol) in toluene (120 ml) was added slowly methanesulfonyl chloride (10.6 ml, 136 mmol) via a syringe. The rate of the addition was kept at such rate that the temperature of the reaction mixture did not rise above 20° C. After completion of the addition, the temperature was kept at room temperature for one and a half hours. Water (50 ml) was added to the mixture, and an emulsion formed that was broken by the addition of 100 ml toluene. The aqueous layer was extracted with 100 ml toluene and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness, leaving a white solid residue identified as the product (30.5 g, 87%), and which was used as such in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O1CCCC1>C(OCC)(=O)C.O>[CH3:1][S:2]([O:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Commercially available methanesulfonyl chloride (6.35 mL, 82.0 mmol) and triethylamine (26.0 mL, 186 mmol) were added to a mixture of commercially available tert-butyl 4-hydroxy-1-piperidine carboxylate (15 g, 74.5 mmol) and tetrahydrofuran (200 mL) at 0° C., and the mixture was stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture for partition. The organic layer was dried and filtered by conventional methods. The solvent was evaporated, and the residue was collected by filteration and washed with n-heptane to obtain the title compound (19.8 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].CC(C)=O.C(O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: CC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
50.0 g. (0.248 m) 5-chloro-2-mercaptobenzothiazole and 53.0 g. (0.248 m) α-bromophenylacetic acid are dissolved in 1.51. acetone and the solution is heated for 4 hours in the presence of 50 ml. glacial acetic acid. The solution is concentrated to a smaller volume (about 200 ml) and the residual solid (90 g.) is collected. The resulting salt is suspended in 1 l of water and the mixture is stirred at room temperature overnight. The collected solid is recrystallized from 2.5 l. acetonitrile to give a total of 64 g (85% yield) of title compound melting at 190°-2° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].OCC(CO)(CO)CO.[Sn+2]>O>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9]
Reactant: C[C@H](O)C(=O)O
Agent: C=C(CC(=O)O)C(=O)O
Agent: OCC(CO)(CO)CO
Agent: [Sn+2]
Solvent: O
Product: CC(O)C(=O)O
Temperature: 180 °C
Reaction time: 24 h

Procedure:
Into a 2 liter Rotavapor equipment, used as the reactor, 437.5 g of L-lactic acid was added (88% water solution corresponding to 89 mole-%), 47.9 g of itaconic acid (9 mole-%), 14.5 g of pentaerythritol (2 mole-%) and 0.19 g of tin(II) octoate. Dry nitrogen was led into the reactor and a 500 mbar absolute pressure was established. The reactor vessel was partly immersed in an oil bath with a temperature of 90° C. The temperature of the oil bath was increased at a rate of 30° C./h to 120° C., and the reaction mixture was mixed by starting the rotation at a speed of 100 rpm. The temperature of the oil bath was evenly increased by 15° C./h until 180° C., where it was kept until the end of the polymerisation. The pressure was decreased every hour by the following steps: 500 (start)—500-450-400-350-290-190-140-90-60-50-40-30 mbar, at which pressure it was kept to the end of the polymerisation. Bubbling of nitrogen was continued throughout the polymerisation and the formed water was collected as it evolved. Total polymerisation time was 24 hours.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=1[O:21][CH3:22]>ClCCl.C(OCC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:14]=1[O:21][CH3:22]
Reactant: COc1cc(CO)ccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)ccc1Cl
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of pyridinium chlorochromate (1.37 g, 6.34 mmol) in dichloromethane (35 mL) was treated with Celite (2.0 g) and stirred at rt. A solution of (4-chloro-3-methoxyphenyl)methanol (730 mg, 4.23 mmol) in dichloromethane (5 mL) was added in one portion, and the resulting mixture was stirred at rt for 3 h. After this time, the mixture was diluted with diethyl ether, and stirred vigorously. The mixture was then filtered through a pad of silica gel and the collected solids were rinsed with additional diethyl ether. The combined filtrates were concentrated under vacuum to provide 4-chloro-3-methoxybenzaldehyde as a pale tan-yellow solid (630 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3 H) 7.41 (dd, J=7.9, 1.8 Hz, 1 H) 7.45 (d, J=2.0 Hz, 1 H) 7.55 (d, J=7.6 Hz, 1 H) 9.95 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
Azetidine (0.25 g, 4.35 mmol) was added to a solution of sodium hexamethyldisilylazide (0.85 g, 4.6 mmol) in THF (10 mL) at 0° C. and reaction mixture stirred for 10 minutes. 4-fluorobenzenesulfonyl chloride (0.85 g, 4.35 mmol) was subsequently added and the reaction mixture was allowed to warm up to ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated and then dried (MgSO4), filtered and evaporated to give a waxy, yellow solid (75 mg).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[Br:13][C:11]1[CH:12]=[C:3]([NH:2][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:4]([CH3:14])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: Br
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C

Procedure:
Scheme 1 below outlines a particular embodiment for the production of the free base of Compound I, as well as the hydrobromide of Compound I. Briefly, methyl 3-amino-5-bromo-2-methylbenzoate (1) is reacted with dihydro-2H-pyran-4(3H)-one under reductive amination conditions to form methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (2) in step 1. In step 2, reductive amination is again used to form 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (3). This compound is then reacted under Suzuki coupling conditions in step 3 to form methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxylate (4), which is hydrolyzed to the corresponding acid (5) in step 4. In step 5, acid (5) is reacted under amide coupling reaction conditions with 3-(aminomethyl)-4,6-dimethyl-dihydro-pyridin-2(1H)-one hydrochloride to form Compound I.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:2].[Cl-].[NH4+]>C(O)C.C1COCC1.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccncc2[nH]1

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 13, 500 mg, 2.1 mmol) in ethanol (20 mL) and THF (10 mL) was added saturated ammonium chloride solution (10 mL) and iron powder (700 mg, 12.6 mmol). The reaction was heated under reflux for 1 h, then filtered through celite and washed through with hot ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.44 (3H, t), 4.43 (2H, q), 7.21 (1H, s), 7.69 (1H, d), 8.12 (1H, d), 8.80 (1H, s).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)[CH3:8].[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].C[O-].[Na+]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:7]([CH3:8])[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h
Yield: 103.5 %

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol (from 2.44 g of sodium and 90 ml of methanol). The solution was stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3× 300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=[O:12])=[N:3]1.[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[N:3]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(=O)O)c2ccccc21
Yield: 92.1 %

Procedure:
A solution of 1-methylindazole-3-carboxylic acid, methyl ester (1.00 g, 0.0053 mol) was stirred in a mixture of methanol (10 mL)/2 N NaOH solution (120 mL) at reflux temperature for 2 hours. After cooling, the mixture was diluted with water (100 mL) and acidified with 6 N HCI solution. The white solid that formed was collected by filtration and dried under ambient conditions for 6 days to give 0.86 g (92% yield) of the product; mp 215°-216° C.
Reaction SMILES: C([NH:4][C:5]1[CH:21]=[CH:20][C:8]([S:9]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>O>[C:13]([NH:12][S:9](=[O:10])([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:21][CH:20]=1)=[O:11])(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(=O)NS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(=O)NS(=O)(=O)c1ccc(N)cc1

Procedure:
N4 -acetyl-N1 -hexanoylsulfanilamide from the previous step was treated with sodium hydroxide (24.6 g) in D.I. water (200 mL) while heating to reflux. After 3 hours reaction time, the heating was stopped and the solution pH adjusted to 8 with 2N HCl. The solution was cooled in an ice bath and then filtered to remove sulfanilamide. The filtrate was acidified with aqueous HCl to pH 2 to precipitate the product, N1 -hexanoylsulfanilamide, 37.9 g. This material was recrystallized from hot ethanol (75 mL) and precipitated by addition of 40 mL D.I. water to afford recrystallized N1 -hexanoylsulfanilamide, 24.8 g (43% overall yield). H1 -NMR indicated a purity >90%.