Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:9]1[CH2:14][CH2:13][C:12]2[S:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)C.C(O)C.[OH-].[K+]>O>[ClH:24].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:8]([N:9]1[CH2:14][CH2:13][C:12]2[S:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)[CH2:7][CH2:6][C:5]([CH3:25])([CH3:26])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Product: Cl
Temperature: 25 °C
Yield: 139.3 %

Procedure:
5-(2-Chlorophenyl)-5-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylpentanoic acid ethyl ester (1.0 g, 2.46 mmol) was dissolved in water (5 mL) and ethanol (5 mL) that contained potassium hydroxide (1 g). The mixture was heated to reflux for 6 hours. After cooling to room temperature, the ethanol was removed under reduced pressure. Water (25 mL) was added and the solution was acidified to pH=5 to 6 with concentrated hydrochloric acid. The product was extracted with dichloromethane (2×25 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated. The crude product (1.06 g) was purified by column chromatography on silica gel (20 g), eluting with heptane/ethyl acetate (1:1). The product containing fractions were combined, concentrated, and dissolved in dichloromethane (25 mL). The dichloromethane solution was acidified with hydrochloric acid (2N) in diethyl ether (6 mL). The solvents were removed under reduced pressure. The remaining solid was dried to a constant weight at room temperature under high vacuum to provide 5-(2-chlorophenyl)-5-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylpentanoic acid, hydrochloride salt (Compound Ia hydrochloride, 0.71 g, 69.6% yield) as a off-white solid. 1H NMR (300 MHz, DMS-d6/TMS): δ=12.20 (br s, 1H), 11.83 (br s, 0.5H), 11.61 (br s, 0.5H), 8.10 (m, 1H), 7.77-7.41 (m, 4H), 6.97 (d, 1H, J=4.5 Hz), 6.81 (d, 1H, J=4.5 Hz), 4.90-4.70 (m, 1.5H), 4.42-4.37 (m, 0.5H), 4.11-4.01 (m, 1H), 3.90-3.80 (m, 0.5H), 3.51 (m, 0.5H), 3.20-2.84 (m, 2H), 2.37 (m, 1H), 2.14 (m, 1H), 1.28 (m, 1H), 1.04 (s, 3H), 1.02 (s, 3H), 0.90 (m, 1H). (mixture of rotational isomers). 13C NMR (75 MHz, DMS-d6/TMS): δ=177.64, 134.50, 131.23, 130.89, 129.72, 129.38, 128.02, 127.33, 125.06, 124.68, 64.62, 63.52, 54.63, 49.73, 48.54, 47.93, 47.20, 40.72, 35.21, 25.90 (d), 24.78, 24.37, 21.79, 21.31 (d), 14.99. MS (MMI-TOF): Calculated for C20H25NO2Cl2S (MH+): 378.1289. found 378.1271. CHN analysis: Calculated; 57.97; C, 6.08; H, 3.38; N, 17.11; Cl. Found; 56.07; C, 6.25; H, 3.12; N, 18.55; Cl, Best Fit for CHN Data: C20H25Cl2NO2S+0.65H2O+0.05 HCl
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:34]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:10]=1[C:8]#[N:9])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Example 16c, 2.26 g, 6.03 mmol) in anhydrous DCM (50 mL) was added triethylamine (4.2 mL, 30.1 mmol) at room temperature. The reaction mixture was cooled down to 0° C. and butyryl chloride (0.95 mL, 9.05 mmol) was added and the solution stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was diluted with EtOAc (150 mL), the organic layer was washed successively with water, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product (1.5 g. 75%). MS 332 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution/suspension of 3.74 g (17.5 mmol) 2-nitro-4'-methylbiphenyl, 123 mg (0.9 mmol) AIBN, and 3.43 g (19.3 mmol) NBS in 180 mL CCl4 was refluxed for 30 minutes. The mixture was cooled to room temperature, was filtered through a medium fritted funnel, was washed with water, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 7% ethyl acetate in hexanes to give 4.71 g (92% yield) of the title compound as a light yellow crystalline solid. Rf 0.21 in 10% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain. 1H-NMR (400 MHz, CDCl3): δ7.88 (m, 1H), 7.63 (m, 2H), 7.52 (m, 1H), 7.45 (m, 2H), 7.31 (m, 2H), 4.54 (s, 2H); a small singlet at d 6.69 (benzylic proton) is observed for for the dibrominated material.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[C:5]=2[CH:6]=1.O1CCOCC1.C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=1.ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2([OH:11])[C:5]3[CH:6]=[C:2]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=4)[S:3][C:4]=3[CH2:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: OC1(c2ccc(Cl)cc2)CCCc2sc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3(O)c2ccc(Cl)cc2)ccn1
Temperature: 25 °C
Yield: 9.8 %

Procedure:
In a 100 mL round bottomed flask were placed 2-bromo-4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (640 mg, 1.9 mmol) and 1,4-dioxane (10 mL). To the mixture were added N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (925 mg, 3.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (198 mg, 0.242 mmol). The mixture was refluxed for 16 hr with vigorous stirring. The mixture was allowed to cool to rt and then diluted with EtOAc (100 mL). The resulting solution was washed with H2O (50 mL×2). The combined aqueous phases were extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (50 mL) and dried over MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with a 30% to 100% EtOAc/hexane to obtain crude title compound (ca 500 mg). About 100 mg of this material was purified by HPLC (AA) to obtain pure title compound (74 mg; 10%). LCMS: (AA) ES+ 399, 401; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.51 (br s, 1H), 8.23 (s, 1H), 8.20 (d, 1H), 7.36 (d, 2H), 7.30 (d, 2H), 7.19 (dd, 1H), 7.14 (s, 1H), 5.85 (s, 1H), 2.83-2.90 (m, 2H), 2.07 (s, 3H), 1.85-2.01 (m, 3H), 1.65-1.70 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.[Sn](Cl)[Cl:41].[C:43](OCC)(=O)C>>[ClH:41].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:43][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: CCOC(C)=O
Reactant: Cl[Sn]Cl
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A mixture of Compound B (660 mg, 1.68 mmol), tin (II) chloride (1.52 g, 6.7 mmol) and ethyl acetate (75 mL) was stirred at room temperature for 18 hours and quenched with aqueous and then solid potassium carbonate (5 mL, then 5 gms). The mixture was filtered, the filtrate partitioned and the organic phase dried (MgSO4), concentrated in vacuum, and purified using flash chromatography (3:1 hexane:ethyl acetate) to provide Compound C (315 mg, 52%) as a clear oil.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(COc2ccc(Br)cn2)cc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a diethyl ether (150 mL) solution of 5-bromo-2-(4-fluoro-benzyloxy)-pyridine (3.75 g 13.3 mmol) described in Manufacturing Example 58-1-1 was added n-butyl lithium (2.55 M n-hexane solution, 6.26 mL, 16.0 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (1.54 mL, 20.0 mmol) was then added dropwise and stirred for 5 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.23 g, 72.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[CH3:11].NOS(O)(=O)=O.CO.[N:20]1C=CC=[CH:22][CH:21]=1>COC(OC)(N(C)C)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][N:20]=[C:21]([CH3:22])[N:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(N)=S)ccc1Br
Reactant: c1ccncc1
Agent: COC(C)(OC)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1nsc(-c2ccc(Br)c(C)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromo-3-methylbenzenecarbothioamide (1.20 g) in dimethylacetamide dimethyl acetal (2 ml) and dichloromethane (30 ml) was stirred under nitrogen at room temperature for 7 h. The solvent was evaporated in vacuo to give a dark brown oil to which was added hydroxylamine-0-sulphonic acid (0.88 g), methanol (20 ml) and pyridine (0.83 ml) and the mixture stirred at room temperature under nitrogen for 16 h. After evaporation, aqueous potassium carbonate was added and the mixture was extracted with dichloromethane. The combined extracts were dried and evaporated to give a brown residue which was purified by column chromatography on silica eluting with hexane: ethyl acetate (4:1) to give the title compound as an orange solid (0.8 g).
Reaction SMILES: [CH:1]12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C(OC([N:26]1CCC2C(NC2)C1)=O)(C)(C)C.ClC1N=C(C)C=C(C)N=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:14][C:15]1[CH:16]=[C:11]([CH3:12])[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][NH:3][CH2:2]3)[CH2:7]2)[N:26]=1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: Cc1cc(C)nc(Cl)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C12H18N4, 218.3; m/z found, 219.2 [M+H]+. 1H NMR (CDCl3): 6.32 (s, 1H), 4.25-4.16 (m, 1H), 4.03 (t, J=7.6, 1H), 3.75 (dd, J=7.9, 3.1, 1H), 3.62 (dd, J=14.5, 1.6, 1H), 3.15-3.05 (m, 1H), 2.94 (dd, J=14.5, 3.8, 1H), 2.67-2.56 (m, 2H), 2.28 (s, 6H), 2.11-1.98 (m, 2H), 1.77-1.64 (m, 1H).
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C([O-])(O)=O.[Na+:15].[O-:16][S:17](S([O-])=O)=[O:18].[Na+].[Na+].[Br-]>C(#N)C.O>[OH:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([F:10])([F:9])[S:17]([O-:18])=[O:16].[Na+:15]
Reactant: OCCC(F)(F)C(F)(F)Br
Reactant: O=S([O-])S(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 55 °C

Procedure:
4-Bromo-3,3,4,4-tetrafluoro-1-butanol (19.92 g, 88.54 mmol) was added to a slurry of NaHCO3 (22.31 g, 265.6 mmol) and Na2S2O4 (46.25 g, 265.6 mmol) in 60 mL of acetonitrile and 88 mL of water. The mixture was heated at about 55° C. for two days in a wax bath without stirring due to the large amount of solids present. 19F NMR spectra showed almost no conversion to product. The temperature was then increased to about 80° C. As the temperature increased, sufficient of the inorganic salts (NaHCO3 and Na2S2O4) dissolved to allow for stirring of the mixture. Additional sodium dithionite (17 g) and sodium bicarbonate (15 g) were added. NMR spectra showed that further reaction had occurred. The reaction mixture was allowed to cool to ambient temperature and additional water (100 mL) and acetonitrile (100 mL) were added so that all the solid material dissolved. NMR spectra were taken of each layer. The aqueous layer contains sulfinate and perhaps a small amount of sulfonate, but no starting bromide, while the acetonitrile layer shows a considerable amount of starting material. The layers were separated. The aqueous layer was set aside, and additional sodium dithionite (30 g) and sodium carbonate (38 g) were added to the acetonitrile layer (200 mL) along with about 100 mL of water. The reaction mixture was heated at about 85° C. overnight. The solution was cooled, filtered, combined with the previously separated aqueous layer, and the volatiles were removed on a rotary evaporator. The resulting crunchy solid was washed with about 200 mL of ether and dried under vacuum.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[C:7]([CH3:29])=[CH:6][N:5]=1)(=O)[CH3:2].[C:30](OC(OC(C)(C)C)N(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:51][C:52]([CH3:57])([CH3:56])[C:53]([NH2:55])=[NH:54]>CN(C)C=O>[C:52]([C:53]1[N:55]=[C:1]([C:4]2[CH:9]=[C:8]([N:10]3[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])=[C:12]([Cl:27])[C:11]3=[O:28])[C:7]([CH3:29])=[CH:6][N:5]=2)[CH:2]=[CH:30][N:54]=1)([CH3:57])([CH3:56])[CH3:51]
Reactant: CC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(-c2ccnc(C(C)(C)C)n2)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of 2′-acetyl-3-chloro-4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2H-1,4′-bipyridin-2-one (from step 7) (0.024 g, 0.057 mmol) in dimethylformamide (0.5 mL) was added N, N dimethylformamide di-tert-butyl acetal (0.02 g, 0.1 mmol) and heated at 60° C. for 2 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in toluene (1 mL) and the solvent was removed in vacuo. The resulting residue was dried in vacuo for 2 h. It was dissolved in DMF (1 mL) and potassium carbonate (0.025 g, 0.18 mmol) and 2,2,2-trimethylacetamidine hydrochloride (0.02 g, 0.14 mmol) were added. This mixture was heated at 80 C. for 12 h under nitrogen. DMF was removed in vacuo and the residue was partitioned between water (5 mL) and ethyl acetate (15 mL). The organic phase was washed with water, dried with magnesium sulfate, and concentrated. The resulting residue was purified by silica-gel flash chromatography using 3% methanol in ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to give 0.011 g of the title compound. ES-MS, m/z=511 (M+H).
Reaction SMILES: [N:1]1C=CC=C(C(N)C)C=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=O)[CH3:21])=[CH:12][CH:11]=1.N.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([NH2:1])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(N)c1cccnc1
Reactant: CC(=O)c1ccnc2ccccc12
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1ccnc2ccccc12

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-quinolin-4-yl-ethanone, (1.71 g, 10 mmol, Aldrich), 2 M ammonia solution in methyl alcohol, (40 mL, 80 mmol, Aldrich), acetic acid (10 mL, J. T. Baker) and sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich). The title compound obtained in form as light yellow solid in 100% yield (1.72 g, 10 mmol).
Reaction SMILES: [O-:1][CH2:2][CH2:3]CC.[K+].[C:7]([NH:10][C:11]1[CH:12]=[C:13]([F:23])[C:14]([F:22])=[C:15]2[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]2)(=[O:9])[CH3:8].[N:24](OCCCC)=O.Cl>C1COCC1.C(O)(C)(C)C>[C:2]([NH:24][CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[CH:12]=[C:13]([F:23])[C:14]=2[F:22])[C:19]1=[O:21])(=[O:1])[CH3:3]
Reactant: CC(=O)Nc1cc(F)c(F)c2c1C(=O)CCC2
Reactant: CCCCON=O
Reactant: CCCC[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(F)c(F)c2c1C(=O)C(NC(C)=O)CC2
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a mixed solution of 15 ml of a THF solution and 1.5 ml of tert-butanol containing 309 mg of potassium-butoxide was added slowly in a nitrogen stream at 0° C. 300 mg of the compound prepared in (7) above dissolved in 7.5 ml of THF. After stirring for 10 minutes at the same temperature, 0.22 ml of n-butyl nitrite was dropwise added to the mixture, followed by further stirring for 1.5 hours, during which the temperature was slowly raised to 20° C. The reaction mixture was adjusted to pH 1 with the addition of 1N hydrochloric acid, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. To the residue obtained by evaporating the solvent was added a mixture of 15 ml of acetic acid and 15 ml of acetic anhydride, and was added about 1 gm of zinc powder, followed by stirring at 20° C. for 18 hours. Insoluble substances were removed by filtration, the solvent was evaporated, and the residue was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a chloroform-methanol (97:3) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 311 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][OH:21])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].OCCNC(=O)OC(C)(C)C.Br[CH2:34][C:35]#[C:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Br)C#C>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:34][C:35]#[C:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2]
Reactant: BrCC#Cc1ccccc1
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCO
Agent: C#CCBr
Agent: CC(C)(C)OC(=O)NCCO
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1ccccc1

Procedure:
The general method described in Part A of Example 81 was followed, using 2-(8-ethoxymethyl-5,6-dimethyl-7H-imidazo [4,5-c]tetrazolo [1,5-a]pyridin-7-yl)ethanol (4.51 g, 15.5 mmol) in lieu of tert-butyl 2-hydroxyethylcarbamate and 3-bromo-1-phenylpropyne, prepared as described in Part A of Example 7, in lieu of propargyl bromide. The crude product was triturated with diethyl ether, isolated by filtration, and dried under reduced pressure to provide 5.93 g of 8-ethoxymethyl-5,6-dimethyl-7-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[CH:20]1[CH2:21][CH2:22][N:23]([CH2:9][C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:24][CH2:25]1
Reactant: COc1nccnc1C=O
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1nccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
After dissolving 186 mg of 3-methoxypyrazine-2-carboxaldehyde and 230 mg of (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in 3 ml of 1,2-dichloroethane, 0.08 ml of acetic acid and 373 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (296 mg, 82% yield).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: O=C(NNc1ccc(F)cn1)N1CCCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(N3CCCCC3)n2c1
Reaction time: 2 h
Yield: 48 %

Procedure:
Hexachloroethane (826 mg, 3.92 mmol) was added portionwise to a solution of Intermediate 3a (466 mg, 1.95 mmol), triphenylphosphine (1.03 g, 3.92 mmol) and triethylamine (1.1 mL, 7.83 mmol) in dry THF (30 mL) at RT, and the mixture stirred for 2 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as pale orange coloured gum (206 mg, 48%). LCMS (Method 1): Rt 2.44 min, m/z 221 [MH+].