Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].Cl>O.C(O)C>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH:32][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[CH:3][CH:4]=1)[CH3:28]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: CCN(CC)CCN
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCNc1ccc(NCCN(CC)CC)c2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Yield: 7.6 %

Procedure:
A mixture of 5 g (0.021 mol) of 1,4-dihydroxyanthracene-9,10-dione and 2 g (0.014 mol) of sodium dithionite in 20 ml water is stirred whilst heating under nitrogen at 90° C. until the mixture turns from orange to brown indicating the presence of 2,3-dihydro(leuco)-1,4-dihydroxyanthracene-9,10-dione. To this reaction mixture is added dropwise 20 g (0.17 mol) of 2-(diethylamino)-ethylamine over a 30 minute period. The mixture is heated at 50°-55° C. for 2 hours and 20 ml of ethanol are added. The solution is then aerated and 200 ml of 2M hydrochloric acid are added. The acidic mixture is washed with 3×200 ml of diethylether followed by 3×200 ml of chloroform. The aqueous phase is made alkaline by the addition of sodium hydroxide solution and extracted with 3×200 ml chloroform. The mixture is evaporated in vacuo to a 5 ml volume and subjected to flash chromatography using a column of 70-230 mesh (60 A) silica gel (SiO2) and an eluting solvent of chloroform followed by chloroform:methanol (1:1 v/v). The blue black material removed from the column in chloroform/methanol is evaporated in vacuo to yield 0.7 g of the title compound, m.p. 107.5°-108.5° C.; λmax λmax (deionised water) (E/cm/M) 256 nm (50950), 584 nm (18650).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13](OCC)=[O:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[CH2:1]([O:8][NH:9][C:10](=[O:11])[CH:12]([CH2:13][OH:14])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C(=O)NOCc1ccccc1)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(CO)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of 2-benzyloxycarbamoylheptanoic acid, ethyl ester (12.29 g, 39.98 mmol) in THF (400 mL)) was added LiBH4 (8.70 g, 399.8 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Ice-water (500 mL) was then added to the reaction mixture (warning: vigorous evolution of gas). The aqueous layer was extracted with EtOAc (400 mL×2). The organic extracts were washed with water, brine, and dried over MgSO4. After removing the solvent under reduced pressure, flash column chromatography (hexane:EtOAc 1/2) yielded 5.36 g (51%) of the title compound. 1H NMR (400 MHz, CHCl) δ 9.22 (br s, 1H), 7.41–7.28 (m, 5H), 4.89 (q, J=10.6 Hz, 2H), 3.70–3.37 (m, 3H), 2.17 (m, 1H). 1.54 (br s, 1H), 1.27 (m, 6H), 0.88 (t, J=6.9 Hz). MH+ 266.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[N:8]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:41])[F:42])=[CH:40][CH:39]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Temperature: 0 °C

Procedure:
4,6-dichloro-3H-imidazo[4,5-c]pyridine (500 mg, 2.6 mmol), PPh3 (762 mg, 2.91 mmol) and THF (20 mL) were combined and stirred under a nitrogen atmosphere. A solution of 4-trifluoromethyl benzyl alcohol (513 mg, 2.91 mmol) in THF (5 mL) was added at rt. The reaction mixture was cooled to 0° C., and diisopropyl azodicarboxylate (587 mg, 2.91 mmol) was added dropwise. The reaction was warmed to rt and stirred overnight under N2. The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was dissolved in EtOAc (20 ml), p-toluenesulfonic acid (500 mg, 2.91 mmol) was added at rt, and the mixture was stirred for 3 h. The precipitate which formed was collected by filtration and rinsed with EtOAc. The collected precipitate was slurried in EtOAc (50 mL) and was stirred vigorously with aqueous sat'd NaHCO3 (5 mL) for 30 min. The organic layer was separated, and the aqueous layer was extracted several times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography with 20% to 100% EtOAc/hexanes to obtain the desired isomer, 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (400 MHz, CDCl3): δ8.85 (s, 1H); 7.96 (s, 1H); 7.71 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.89 (s, 2H). MS APCl calc'd. for C14H8Cl2F3N3 [M+H]+ 346, found 346.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: ON=Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Br)cc1F
Yield: 81.4 %

Procedure:
In a fashion similar to that for preparation 14, 2-Fluoro-4-bromo-benzaldehyde oxime (2.77 g, 12.7 mmol), N-chlorosuccinimide (1.76 g, 13.2 mmol), and DMF (25 ml) gave 2-fluoro-4-bromo-benzoyl chloride oxime (2.61 g, 81%) after filtration through a plug of silica gel eluting with hexanes/Et2O.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:15].[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:15])=[CH:20][CH:19]=1)#[N:17]
Reactant: CCCNS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h

Procedure:
According to general procedure B, 4-bromo-3-fluoro-N-propylbenzenesulfonamide (174 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-propylbenzenesulfonamide was provided after purification. HRMS: calcd for C15H16FN3O2S, 321.09472; found (EI, M+.), 321.0947. HPLC purity 99.7% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@@H:16]12[NH:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: [H][H]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.21-4.02 (m, 1H), 3.84-3.59 (m, 3H), 3.47-3.36 (m, 1H), 3.33 (dd, J=8.3, 4.4 Hz, 1H), 3.28-3.20 (m, 1H), 2.91-2.71 (m, 2H), 1.94-1.81 (m, 1H), 1.81-1.68 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(O)[CH:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[CH:16][CH:17]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CC1CNCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 66.5 %

Procedure:
To a solution of 1-benzyl-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (1.02 g, 3.41 mmol) in ethanol (18 mL) at 80° C. was added concentrated HCl (18 mL, 592 mmol). The reaction mixture was refluxed for 2 hour and then cooled to ambient temperature. The organic solvent was removed in vacuo. The aqueous solution was basified with concentrated NaOH to pH>9 then extracted with DCM (50 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in EtOH (2 mL) and acetic acid (0.2 mL). The reaction mixture was hydrogenated with Pd/C (10%) in an H-cube™ apparatus at 60° C. for 3 minutes. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 for 2.5 min then 10% to 15% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min then 15% to 45% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min at 25 mL/min; APCI positive mode detection; Xterra prep. MS C18 19×50 mm column) to afford 4-(4-fluorophenyl)-3-methylpiperidine (0.438 g, 66%). RP-HPLC (Table 1, Method a) Rt 1.43 min; m/z: (M+H)+ 194.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21](OC)=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[NH:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:29][NH:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:22][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)NN
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
3-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-methoxypyridazine was heated with t-butyl carbazate to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]=[C:13]([CH3:15])[CH3:14]>C(OCC)C>[Br:6][CH2:7][CH2:8][C:9]([O:11][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:10]
Reactant: O=C(O)CCBr
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCBr
Temperature: -20 °C

Procedure:
7 ml of sulfuric acid were added to a solution of 100 g of 3-bromopropionic acid in 200 ml of diethyl ether, and the reaction mixture was cooled to -20° C. Then 123 ml of liquified isobutene were added. The reaction mixture was stirred at room temperature in a pressure vessel for several hours. Subsequently, for working up, the reaction mixture was poured into dilute ice-cold aqueous sodium hydroxide solution. The ether phase was separated and the aqueous phase was extracted once more with ether. The combined organic phases were washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was distilled under reduced pressure. 100 g of tert-butyl 3-bromopropionate were obtained, boiling point (20)=75° to 77° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]#[N:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(N)=O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C#N)cc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of EXAMPLE 1F in acetonitrile (20 mL) at 0° C. was treated with DMF (0.543 mL, 7.02 mmol) and oxalyl chloride (0.561 mL, 6.43 mmol), stirred for 5 minutes, treated with pyridine (1.04 mL, 12.866 mmol), and stirred for another 50 minutes at 0° C. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the aqueous layer extracted with ethyl acetate three times and the combined organic layers dried (MgSO4), filtered, and concentrated to give the desired product as a residue that was utilized directly in the next step without further purification. MS (ESI) m/e 325 (M+H)+.
Reaction SMILES: [C:1]1([NH:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](OCC)(=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(O)(C)C>[N:17]1[CH:18]=[CH:19][C:14]([C:13]2[NH:12][N:11]=[C:1]3[C:10]4[C:5]([CH:4]=[CH:3][C:2]=23)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:15][CH:16]=1
Reactant: NNc1cccc2ccccc12
Reactant: CCOC(=O)c1ccncc1
Solvent: CC(C)O
Product: c1ccc2c(c1)ccc1c(-c3ccncc3)[nH]nc12

Procedure:
A solution of 16 grams (0.10 mole) of 1-naphthyl hydrazine, 15.1 grams (0.10 moles) of ethyl isonicotinate and 300 ml. of isopropanol are stirred and refluxed for 48 hours. The solvent is removed in vacuo and the resultant 2-(1-naphthyl)-isonicotinic acid hydrazide is added to 125 ml. of phosphorous oxychloride and stirred and refluxed for about 15 hours. The reaction mixture is then concentrated in vacuo and the resultant simi-solid dissolved in about 250 ml. methylene dichloride. The methylene dichloride layer is washed with 100 ml of cold 2N potassium hydroxide, 100 ml. of water, dried with magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethanol/ether yields 3-(4-pyridyl)-2H-naphtho[1,2-c]pyrazole, m.p. 271°-273°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:6][C:5]=1[C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=[CH:19][C:18]=1[O:30][CH2:31][CH3:32])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:31]([O:30][C:18]1[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][C:17]=1[C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:32]
Reactant: CCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(CCCC(=O)O)cc1-c1cc(CCCC(=O)O)ccc1OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
To 10 ml of an ethanol solution containing 183.3 mg (0.4147 mmol) of 2,2'-diethoxy-5,5'-bis(3-methoxycarbonylpropyl) biphenyl obtained in Reference Example 5, there was added 3.3 ml (3.3 mmol) of 1N sodium hydroxide solution and the mixture was agitated at room temperature for 24 hours. The solvent of the reaction mixture was evaporated off under reduced pressure and, to the resulting evaporated residue, water was added. The solution obtain was acidified by adding 1N hydrochloric acid to a pH of 1-2. The thus-formed precipitate was filtered, washed with water and dried, whereby 164 mg (0.3966 mmol, 96%) of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].CCN=C=NCCCN(C)C.Cl.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:60])[C@@H:32]1[CH2:39][N:38]2[C:40]3[CH:41]=[C:42]([C:53](O)=[O:54])[CH:43]=[CH:44][C:45]=3[C:46]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[C:37]2[C:36]2[CH:56]=[CH:57][CH:58]=[CH:59][C:35]=2[O:34][CH2:33]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:53]([C:42]1[CH:43]=[CH:44][C:45]2[C:46]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)=[C:37]3[C:36]4[CH:56]=[CH:57][CH:58]=[CH:59][C:35]=4[O:34][CH2:33][C@H:32]([N:31]([CH3:60])[CH2:30][CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:39][N:38]3[C:40]=2[CH:41]=1)=[O:54])(=[O:7])=[O:6]
Reactant: NS(=O)(=O)CCCCl
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCCl)cc3n2C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-chloropropane-1-sulfonamide (1.8 eq), DMAP (2.9 eq) and EDAC.HCl (1.8 eq) were added to a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (prepared as described in Example 1, Step 7) (0.025 M) in DCM. The reaction was stirred under N2 at 40° C. for 2 h, before being allowed to cool. Volatiles were removed in vacuo to leave the crude product as a yellow gum which could be taken on without further purification. (ES+) m/z 687 (M+H)+; 689 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Yield: 92.5 %

Procedure:
6-[3-(4-Chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.0 g, 8.0 mmol) in THF (20 mL), methanol (5.2 mL) and water (19 mL) was treated with lithium hydroxide monohydrate (678 mg, 16.0 mmol) for 8 h at room temperature. Hydrochloride acid (1 N, 25 mL) and water (200 mL) were added to the reaction mixture. The precipitate was filtered off and washed with water and ethyl acetate to afford the title compound (2.67 g, 93%) as a white solid. MS: m/e=359.0 [M−H]−.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH-].[Na+].[N:14]#[C:15]Cl>C(Cl)Cl.O>[C:15]([N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])#[N:14]
Reactant: N#CCl
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1C#N

Procedure:
62.8 g (0.4 mole) of 4-hydroxy-2,2,6,6-tetramethyl piperidine are dissolved in 250 ml of methylene chloride a solution of 16 g (0.4 mole) of sodium hydroxide in 250 ml of water is introduced and 20.5 ml of cyanogen chloride are added dropwise to the mixture at 0° to 5° C. The mixture is stirred until it reaches room temperature, after which the organic phase is separated off, dried with sodium sulphate, filtered and the methylene chloride distilled off, leaving 31 g (42.5% of the theoretical) of 1-cyano-4-hydroxy-2,2,6,6-tetramethyl piperidine. Bp 0.5 = 135° C; melting point 96°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[C:8]2[C:13](=[O:14])OC(C)(C)OC2=O)[NH:6][CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([NH:25][C:13](=[O:14])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cn1)NCc1ccccc1
Yield: 96.4 %

Procedure:
A flask was charged with 5-(5-bromopyridin-2 (1H)-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.039 g, 3.46 mmol), benzylamine (0.50 mL, 4.58 mmol), and toluene (20 mL). The reaction was brought to reflux under nitrogen for 18 hours, then cooled and placed in a freezer until cold. The product was collected by filtration and washed with hexanes to yield a mass of bright white crystals (1.018 g, 96%).
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:21][CH2:20][C@@H:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]1=[O:33]>COC1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:21][CH2:20][C@@H:19]([O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C@H:12]1[OH:33]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)C(=O)c2cccnc21)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: COC1CCCC1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Lithium borohydride (0.982 g, 45.1 mmol) was added to a cyclopentyl methyl ether (30 mL) solution of (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (5.0224 g, 11.27 mmol) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 2 hours and then an addition 4 hours at room temperature. The reaction was quenched by adding methanol. The reaction mixture was stirred for 0.5 hour. The solvent was mostly removed via vacuum and the crude material was taken up in ethyl acetate, which was washed with water three times. Flash column by ethyl acetate in hexane from 0 to 10% gave the desired product (3.28 g, 65%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[H-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cc(Cl)ccc1Oc1cccc(C(F)(F)F)c1
Yield: 32.6 %

Procedure:
2,5-Dichlorobenzoic acid (5 g) and 3-trifluoromethylphenol (4.24 g) were dissolved in xylene and the solution placed under dry oxygen-free nitrogen. Sodium hydride (1.25 g) was slowly added and when effervescence had ceased, cuprous bromide was added and the solution or suspension refluxed for 6 hours. The xylene was removed by low pressure distillation. The solid residue was treated with water and acidified with dilute hydrochloric acid. The resulting oil was extracted into diethyl ether and the ether removed by low pressure distillation to give a light yellow solid which was recrystallised from diethyl ether/petroleum ether to give the title compound (2.7 g), mp, 124° C.