Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=O)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])(C)(C)C>Cl.C(OCC)(=O)C>[CH2:12]([O:11][C@@H:9]([C@H:8]1[CH2:19][O:20][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[NH:7]1)[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (40 mL) of {(1R,2R)-2-benzyloxy-1-[2-(4-chlorophenyl)-2-oxoethoxymethyl]propyl}carbamic acid t-butyl ester (2.61 g) was stirred for 1 hour at room temperature. The solvent was removed under a vacuum, and methanol (30 mL) was added. Under ice-cooling, sodium cyanoborohydride (733 mg) was added, and the resultant was stirred overnight at room temperature. The solvent was removed under a vacuum, and the resultant was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and brine in sequence, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified with silica gel column chromatography (heptane/ethyl acetate 95/5→3/2), and the title compound (1.435 g) was obtained. The physical property values are as follows.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.CO.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[OH-].[Na+]>O.C1(C)C=CC=CC=1.ClCCl>[C:13]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
trans-4-Hydroxyproline (27.5 g, 209.7 mmol) 7 was dissolved into 200 mL of 50% MeOH in water. This was then chilled on ice bath to 0° C. To this mixture was added 85.9 mL of benzyl chloroformate (0.252 mmol; 1.2 eq; 50% vol. in toluene) dropwise. Pellets of NaOH were added to maintain the pH at approximately 9-10 (monitored by litmus paper). The mixture was then allowed to warm to room temperature (22° C.). The mixture was allowed to stir over night at room temperature and the pH closely monitored and maintained at pH=10 by addition of NaOH pellets. The mixture was then diluted by addition of 200 mL water and then extracted with 3×200 mL toluene (to remove remaining benzyl chloroformate). The aqueous layer was then salted with NaCl until saturated and the pH was adjusted to approximately 2 by addition of HCl conc. This was then extracted with 4×200 mL of ethyl acetate. The ethyl acetate washes were then combined and concentrated via rotovap, leaving an oil residue. Dichloromethane (50 mL) was added 4 times to remaining oil and then removed by vacuum. Hexanes (50 mL) was then added to the oil and again removed by vacuum, leaving a sticky foam N-Cbz-4-hydroxyproline crude (quantitative yield) which was then used without any further purification. This residue can also be recrystallized in 10:1, hexanes:CH2Cl2. 1H and 13C NMR spectra were in agreement with 1H and 13C NMR spectra previously reported [Robinson. et al 1998].
Reaction SMILES: [H-].[Na+].OC[CH:5]1[O:9][CH2:8][N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6]1.S1C=CN=[CH:15]1>O1CCCC1>[CH2:15]=[C:8]1[N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][O:9]1
Reactant: c1cscn1
Reactant: CC(C)(C)N1COC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1OCCN1C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
This example illustrates the preparation of the compounds of formula III, via the procedure described in the Application of Berkoz, Lewis and Muchowski, Ser. No. 706,412, filed on even date herewith. In this example 0.012 mole of sodium hydride (50% mineral oil) is stirred in 50 ml. of tetrahydrofuran; under nitrogen, and 0.02 mole of 5-hydroxymethyl-N-t-butyloxazolidine is added. The mixture is then warmed to 50° C until reaction ceases (about 30 minutes) and then cooled to room temperature. 0.01 Mole of 2-ethylsulfinyl-5-[2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazole in 50 ml. of tetrahydrofuran is then added. The mixture is stirred for four hours at room temperature and then poured into 200 ml. of ethyl acetate, then washed with water; dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording a crude residue of 5-(5-[2-endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazol-2-yloxy)methylene-N-t-butyloxazolidine, which is then dissolved in diethyl ether (100 ml.) and hydrogen chloride gas passed over the surface with rapid stirring until no more precipitate is formed. The precipitate is filtered off, washed with ether, then recrystallized from propanol-diethyl ether mixture. The crystals are filtered off and dried under vacuum affording 5-(5-[2-endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thiazol-2-yloxy)methylene-N-t-butyloxazolidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][C:13](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 66.3 %

Procedure:
PtO2 (30 mg) is added to a solution of a E/Z isomers mixture of ethyl (1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-ylidene)acetate (1.5 g, 4.27 mmol) in acetic acid (25 mL); the mixture is maintained under stiffing under a pressure of 1H2 atm. A sample is next extracted and a 1H NRM is done. The mixture is then filtered, diluted with AcOEt, and washed with H2O and with a saturated solution of NaHCO3. The solvent is next evaporated at reduced pressure, giving ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.0 g, 2.83 mmol, purity 66%, oil).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]2[N:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:2]12>CCl.O=[Mn]=O>[O:1]1[CH2:5][CH2:4][N:3]2[N:6]=[C:7]([CH:9]=[O:10])[CH:8]=[C:2]12
Reactant: OCc1cc2n(n1)CCO2
Agent: O=[Mn]=O
Agent: CCl
Product: O=Cc1cc2n(n1)CCO2
Yield: 84.1 %

Procedure:
To the stirred solution of 2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-methanol (2.60 g, 18.5 mmol) in 60 ml of CH3Cl was added 12.9 g of MnO2. Th suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow oil. The product was purified by chromatography. 2.15 g of the product was obtained (84.3%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)O1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O.O1CCOCC1>[NH2:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[CH3:13])[C:18]([OH:20])=[O:19])[CH:11]=2
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)C(C)(C)O1
Reactant: Nc1cc2ccc(Br)cc2cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2cc(N)ncc2c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
A mixture of 7-bromoisoquinolin-3-amine (299.9 mg; 1.344 mmol), 4-methyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (387.1 mg; 1.560 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (51.5 mg; 0.0727 mmol), potassium carbonate (569.3 mg; 4.119 mmol), dioxane (10 mL) and water (1 mL) was stirred at 90° C. for 24 hours and then cooled to room temperature. The reaction mixture was acidified with 10% aqueous citric acid (10 mL). The product was recovered as a red-brown precipitate via filtration, rinsed with water and ethyl acetate, and dried under vacuum to yield 253.4 mg (68%) of the title compound which was carried forward without additional purification. LCMS (ESI): M+H=279.2; 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.81 (d, J=13.1 Hz, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.46 (t, J=9.5 Hz, 2H), 6.67 (s, 1H), 5.96 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9](=[O:18])[C:8]=2[CH:19]=1)=[O:3].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24]>O1CCCC1>[O:18]=[C:9]1[C:8]2[CH:19]=[C:4]([C:2]([O:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:3])[CH:5]=[CH:6][C:7]=2[CH2:13][O:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1OC2
Reactant: CN(C)CCO
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Dissolve 1.0 gm of 9-chlorocarbonyl-6,11-dihydro-11-oxo-dibenz[b,e]oxepin as prepared in Example 10, Step A, in 10 cc of anhydrous tetrahydrofuran with stirring and add 2 ml of N,N-dimethylethanolamine. Stir at room temperature for 18 hours and strip the mixture to dryness. Partition the residue between ether and dilute hydrochloric acid and separate the aqueous layer. Basify the aqueous layer with aqueous ammonia and extract with ethyl acetate. Evaporate the organic phase and chromatograph the residue over silica-gel eluting with 90% chloroform in methanol to obtain the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=C(C=CC=1)CCl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:28][CH3:26])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: COc1cccc(CCl)c1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 3-methoxybenzyl chloride. The title compound, ESI MS (m/z): 483 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][N:7]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:16][CH:15]=4)[C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: O=C1c2cc(Br)ccc2CN1CCc1ccc(Oc2ccccc2)cc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCN(c2ccc3c(c2)C(=O)N(CCc2ccc(Oc4ccccc4)cc2)C3)CC1
Yield: 21.3 %

Procedure:
A mixture of 6-Bromo-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.134 g, 0.33 mmol), 1-methyl piperazine (0.048 mL, 0.43 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.048 g, 0.5 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-(4-Methyl-piperazin-1-yl)-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.03 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.57 (m, 4H), 2.93 (t, 2H), 3.32 (m, 4H), 3.81 (t, 2H), 4.16 (s, 2H), 6.82-7.35 (m, 11H), 7.68 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:6]([OH:11])[C:7]([O:9]C)=[O:8].CO[C:19]1[CH:30]=CC(C(O)C(OC)=O)=C[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2([C:7]([OH:9])=[O:8])[CH2:30][CH2:19][CH2:20][O:11]2)[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1
Reactant: COC(=O)C(O)c1cc(OC)cc(OC)c1
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Product: COc1cc(OC)cc(C2(C(=O)O)CCCO2)c1

Procedure:
2-(3,5-Dimethoxyphenyl)-2-tetrahydrofuroic acid was prepared according to the procedures described in Reference Example 27 substituting 3,5-dimethoxymandelic acid, methyl ester for 4-methoxymandelic acid, methyl ester in Step A.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C>C(O)CCC>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:6][CH2:7][CH2:8][CH3:9])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Solvent: CCCCO
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCC
Yield: 29 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using n-butanol to afford 878 mg (29% yield) of the title compound (313 mg of anti diastereomer, 260 mg of syn diastereomer and 305 mg of the mixture). 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ (higher Rf) 0.89-0.96 (t, 3H), 1.32-1.40 (m, 2H), 1.54-1.63 (m, 2H), 2.37-2.41 (d, H), 2.98-3.04 (q, H), 3.55-3.60 (m, H) 3.77-3.82 (m, H), 4.19-4.22 (m, H), 4.58 (br, 2H), 5.03 (br, H), 5.23-5.40 (m, 3H), 5.87-5.93 (m, H), for syn diastereomer (lower Rf) 0.91-0.95 (t, 3H), 1.34-1.39 (m, 2H), 1.56-1.63 (m, 2H), 2.42-2.50 (m, H), 2.83-2.87 (m, H), 4.07-4.11 (t, H), 4.45-4.50 (m, 0.5H), 4.51-4.70 (m, 2.5H), 5.23-5.35 (m, 2H), 5.42-5.43 (d, H), 5.80-5.95 (m, H); LC-MS: m/z=258 (M+H+) for both of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:45][NH:46][CH2:47][CH:48]([CH3:50])[CH3:49].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:47]([N:46]([CH3:45])[C:19]([C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=1)=[O:20])[CH:48]([CH3:50])[CH3:49]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N(C)CC(C)C)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (260 mg, 0.91 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (350 mg, 1.8 mmol), 1-hydroxybenzotriazole hydrate (140 mg, 0.91 mmol), CH2Cl2 (5 mL) were added N-methylisobutylamine (120 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.4 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by silica gel column (0-60% EtOAc/hexane) to yield a syrup. LC-MS: 354.2 [M+1]+.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+].[BH4-]>C1COCC1.[Co](Cl)Cl.CC(O)=O.O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: COc1cccc(C(O)COc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 70.8 %

Procedure:
5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.15 g, 3.10 mmol) was dissolved in THF (15 ml). Added H2O (15 ml) and sufficient THF to give a clear solution. A small crystal of cobalt chloride was added, followed by 2,2′-bipyridine (109 mg, 0.70 mmol). NaBH4 was added in portions until the blue color persisted. The color gradually faded, but was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC indicated that the reaction was complete the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6, and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.82 g (74%) of the title compound as a white solid. MS (ESI−) for C19H19NO5S m/z 372.0 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:27][CH3:26])=[O:25])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CN
Product: CNC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 45 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and methylamine to provide the final product as a white solid (9.4 mg, 45% yield). MS (apci) m/z=356.1 (M+H).
Reaction SMILES: Cl.[C:2]([C:5](=[N:11][O:12][CH:13]1[CH2:15][CH2:14]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[NH:4])[NH2:3].C(N(CC)CC)C.BrBr.[S-:25][C:26]#[N:27].[K+]>CO.C(OCC)(=O)C>[NH2:27][C:26]1[S:25][N:3]=[C:2]([C:5](=[N:11][O:12][CH:13]2[CH2:14][CH2:15]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(=NOC1CC1)C(=N)N
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 56.3 %

Procedure:
To a solution of ethyl 2-amidino-2-(cyclopropyloxyimino)acetate hydrochloride (syn isomer) (1.44 g) in methanol (11 ml) was added triethylamine (3.06 ml) at -15° C. To the solution was dropwise added bromine (852 mg) at -5° C. After the solution was stirred at -5° C. for 2 minutes, to the solution was added a solution of potassium thiocyanate (518 mg) in methanol (5 ml) at -5° C. The mixture was allowed to be stirred under ice-cooling for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate. The solution was washed successively with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with diethyl ether to give ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(769 mg) as a crystal.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17].O>C(O)C>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:11][CH:12]=1)[CH:16]=[CH2:15]
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc(CCC(C)=O)cc1

Procedure:
p-Hydroxy benzylacetone (1.5 g.), KOH (6 g.) and allyl bromide (1.2 g.) were stirred in ethanol (50 ml) overnight. Water was added and the mixture extracted with ether, which was evaporated to give the compound (1.6 g.) as an oil purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[C:24]([F:27])[CH:23]=[CH:22][C:21]=3[CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3C)c(F)ccc2c1N
Yield: 57.8 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (300 mg, 0.80 mmol) and (2-methyl-5-fluorophenyl)boronic acid (246.8 mg, 1.60 mmol) were reacted to afford the title compound (164.7 mg, 58% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bs, 1H), 7.93 (d×d, J=5.3 Hz, J=9.4 Hz, 1H), 7.54 (apparent t, J=8.6 Hz, 1H), 7.30 (d×d, J=5.6 Hz, J=8.3 Hz, 1H), 6.99-7.09 (m, 2H), 3.44 (apparent q, J=7.0 Hz, 2H), 2.03 (s, 3H), 1.64 (apparent sextet, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=357 (M+H) HPLC 2.78 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH3:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[F:47][C:48]1[CH:49]=[C:50]([S:56](Cl)(=[O:58])=[O:57])[CH:51]=[CH:52][C:53]=1[O:54][CH3:55]>O1CCCC1.ClCCl>[CH:2]1[CH:15]=[CH:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:56]([C:50]1[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:48]([F:47])[CH:49]=1)(=[O:57])=[O:58])[CH:5]2[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1F
Reactant: Cc1nc2ccccc2c2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1F

Procedure:
The intermediate dihydrophenanthridine was prepared from 8-fluoro-6-methylphenanthridine, (Example 32, Method A, Step b, 2.00 g, 9.45 mmol), by treatment with sodium borohydride (1.79 g, 47.4 mmol) and trifluoroacetic acid (2.9 mL, 37.9 mmol) in tetrahydrofuran (38 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (2.7 mL, 19 mmol) and 3-fluoro-4-methoxybenzenesulfonyl chloride (0.78 g, 3.5 mmol, 1.1 equivalents) in dichloromethane (5 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by re-crystallization from a mixture of ethyl acetate-hexane to yield 8-fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine as a homogeneous solid (1.08 g, 84% from the dihydrophenanthridine), m.p. 146-147° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH3:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)c1ccc(C)cn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(C)NCCCCNC(=O)OC(C)(C)C)nc1

Procedure:
Using General Procedure B: Reaction of 1-(5-methyl-pyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668) and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 with NaBH(OAc)3 gave {4-[1-(5-methyl-pyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester as a pale yellow oil.