Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([CH:9]=[O:10])=[N:6][NH:7][CH:8]=1.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.O>CN(C=O)C.C(OCC)(=O)C>[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][N:7]1[CH:8]=[CH:4][C:5]([CH:9]=[O:10])=[N:6]1
Reactant: O=Cc1n[nH]cc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride was added slowly to a clear solution of commercially available 4-bromo-1H-pyrazole-3-carbaldehyde Compound 2a (1 g, 3.56 mmol) in DMF (20 mL). The reaction was stirred at ambient temperature for 20 min; then 2-(trimethylsilyl)ethoxy-methyl chloride (755.7 μL, 4.27 mmol) was added dropwise to the reaction mixture. After the resultant solution was stirred at ambient temperature overnight, water (1 mL) was added to quench the reaction. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, and saturated sodium chloride. The organic solvent was dried over magnesium sulfate. After filtration and evaporation of the solvent in vacuo, the crude product was purified by flash chromatography (10:1 to 4:1 hexane/ethyl acetate) to yield (2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carbaldehyde Compound 3a (620 mg, 57% yield) as white solid. 1H NMR (300 MHz, CDCl3) δ 9.97 (s, 1H), 7.64 (s, 1H), 5.81 (s, 2H), 3.62 (t, 2H), 0.93 (t, 2H), 0 (s, 9H); MS (ESI) m/z: 306.7 (M+H+), 328.7 (M+Na+).
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].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([C:2]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Cl)ccc1Oc1cccc(Cl)c1

Procedure:
To a solution of 2,5-dichlorobenzoic acid (5.0 g) and m-chlorophenol (3.35 g) in dry toluene (100 mls) was added sodium hydride (1.25 g) under dry nitrogen. Cuprous bromide (3.0 g) was then added and the mixture stirred under reflux for 3 hrs. The toluene was then removed by distillation under reduced pressure and the residue acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal extracts were then washed with water and dried over magnesium sulphate. The ether was then removed under reduced pressure and the residue was crystallised from n-hexane to give the title compound.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl.CONC.Cl.CN(C)[CH2:31][CH2:32]CN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](=[O:14])[CH:31]=[CH2:32])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Agent: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)CC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of 2-[4-(ethylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (1.30 g) in N,N-dimethylformamide (20 mL) were added N-methoxymethanamine hydrochloride (582 mg), triethylamine (1.67 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (840 mg) and 1-hydroxybenzotriazole (670 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-0:100, volume ratio) to give a colorless oil. A solution of the obtained oil in tetrahydrofuran (40 mL) was purged with nitrogen, and a 1.0M vinylmagnesium bromide tetrahydrofuran solution (12 mL) was added under ice-cooling. The reaction solution was warmed to room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio) to give the title compound (1.20 g, yield 90%) as a colorless oil. MS: 337 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A stirred solution of 3,4-dinitrophenol (1 g, 5.4 mmol) in 30 ml of anhydrous dimethylformamide was treated with 4-fluorobenzyl chloride (0.86 g, 6.0 mmol) and potassium carbonate (1.13 g, 8.2 mmol). The reaction mixture was stirred at room temperature for 24 hours and then poured into 200 ml of ice-water and this mixture was stirred overnight. The solid was filtered and washed with water to give 1.2 g (76%) of tilted compound as a yellow solid after drying in vacuo. 1H NMR (300 MHz, CDCl3) δ: 8.04 (d, J=9.0 Hz, 1H), 7.40 (dd, J=5.4 and 8.7 Hz, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.18 (dd, J=2.7 and 9.0 Hz, 1H), 7.12 (t, J=8.7 Hz, 2H), 5.16 (s, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:13][C:12]([CH3:17])=[CH:4][CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.10 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H) 4.14 (s, 2 H) 6.92 (s, 1 H) 7.13 (d, J=8.09 Hz, 2 H) 7.28 (d, J=2.94 Hz, 1 H) 7.30 (d, J=5.88 Hz, 2 H) 7.56 (t, J=7.72 Hz, 1 H) 7.67 (d, J=8.46 Hz, 1 H) 7.79 (t, J=7.72 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.22 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:7]=12.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:23][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:7]=23)=[CH:20][CH:19]=1
Reactant: OCc1ccc(F)cc1
Reactant: C=C(C)Cn1c(C)c(C)c2cnnc(Cl)c21
Product: C=C(C)Cn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 38.7 %

Procedure:
The title compound was prepared as a grayish white powder in 38.7% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methyl-2-propenyl)pyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH2:21]([NH2:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:23][CH2:21][CH3:22])[N:14]=1)=[O:8]
Reactant: CCN
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Solvent: C1CCOC1
Product: CCNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 1-(3,4-dichloro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea (Intermediate 6, 0.3 mmol) was taken up in a 2.0 M solution of ethylamine in tetrahydrofuran (5 ml). Reaction was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the crude title compound was taken on as is, ˜75% pure.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(S(C)(=O)=O)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (58 mg, 61%), MS (ISN) m/z=378.4 [(M−H)+], mp 332° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1NCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of benzyl-(4-bromo-2-nitro-phenyl)-amine (276 mg, 0.9 mmol) in 3 ml acetic acid, was added iron (70 mg, 1.2 mmol). The reaction mixture was heated to 40° C. under argon for 2 hours. The mixture was cooled to ambient temperature and filtered through celite and the filtrate was concentrated. The resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to yield crude product that was used in Example 6c.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(NC3CCN(Cc4ccccc4)C3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(NC3CCNC3)ccc2[nH]1
Yield: 54.9 %

Procedure:
A solution of 2.8 g (7 mmol) 5-(1-benzyl-pyrrolidin-3-ylamino)-1H-indole-2-carboxylic acid ethyl ester in 180 ml ethanol and 20 ml acetic acid was hydrogenated over Pd/C for 24 h at room temperature. After filtration and evaporation the residue was taken up in 200 ml 10% NaHCO3 aq. and extracted with 150 ml dichloromethane (DCM). The aqueous phase was washed 7 times with 80 ml DCM each and the combined organic phases were dried over Na2SO4. After filtration and evaporation to dryness the residue was purified over Isolute® SPE (solid phase extraction) eluting with a gradient formed from DCM/2N NH3 in methanol to yield 1.05 g (74%) of the title compound and light brown crystals. MS (m/e): 274.3 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)[C:21]([F:38])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[F:38][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Cl)ccc2F)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.83325 mmol; 176 mg), tert-butyl N-[(3S)-1-(6-chloro-3-fluoro-2-pyridyl)-3-piperidyl]carbamate (0.8378 mmol; 276.3 mg), cesium carbonate (1.6665 mmol; 543.00 mg), Xantphos (0.14165 mmol; 84.500 mg), and tris(dibenzylideneacetone)dipalladium(0) (0.083325 mmol; 77.074 mg) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 110° C. overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (113.1 mg, 16%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7](/[C:19](=[N:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)[CH2:8]CCC1C=CC(OC)=CC=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39](CO)=[CH:38][CH:37]=1>>[C:1]([O:5][C:6](=[O:33])[N:7](/[C:19](=[N:25]\[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])/[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)[CH2:8][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CO)cc1
Reactant: COc1ccc(CCCN(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n2cccn2)cc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)/C(=N\C(=O)OC(C)(C)C)n2cccn2)cc1

Procedure:
The title compound is prepared by an analogous procedure to Intermediate E by replacing 3-(4-methoxyphenyl)-1-propanol with 4-methoxybenzylalcohol. [M+H]+ 431.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][NH2:6])[CH2:3][NH2:4].[C:8](#[N:11])[CH:9]=[CH2:10]>C(O)C>[NH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][NH:6][CH2:10][CH2:9][C:8]#[N:11]
Reactant: C=CC#N
Reactant: CC(C)(CN)CN
Solvent: CCO
Product: CC(C)(CN)CNCCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 2,2 dimethyl-1,3-propanediamine (0.22 mol) and 2-propenenitrile (0.22 mol) in ethanol (250 ml) was stirred overnight at room temperature. The solvent was evaporated. A mixture of 2,2-dimethyl-1,3-propanediamine (0.28 mol) and 2-propenenitrile (0.28 mol) in ethanol (250 ml) was stirred for one hour at room temperature. The solvent was evaporated. The residues were combined. This fraction was purified by distillation, yielding 27.2 g of 3-[(3-amino-2,2-dimethylpropyl)amino]-propanenitrile (intermediate 11).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[C:7](=[O:9])[CH:8]=1.[NH3:15]>CO>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)=[CH:5][N:15]=1
Reactant: O=c1cc(CO)occ1-c1ccoc1
Reactant: N
Solvent: CO
Product: OCc1cc(O)c(-c2ccoc2)cn1
Temperature: 90 °C

Procedure:
A mixture of 2-hydroxymethyl-5-furan-3-yl-pyran-4-one (1.92 g, 10.0 mmole) and 7 M ammonia in methanol (50.0 mL) is stirred and heated in a sealed vessel at 90° C. overnight. The reaction mixture is cooled, evaporated to dryness in-vacuo, taken up in 15% methanol in chloroform and passed thru a pad of magnesol and silica gel eluting with the same solvent. The eluate is evaporated, treated with acetone, filtered, washed with acetone and air dried to give a-grey solid, 1.21 g, (63%); MS (ES+): m/z 192.2 (M+H).
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:14].[NH2:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]1=2>>[ClH:14].[NH2:8][C@H:9]([C:11]([NH:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]1=2)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccc(F)cc21
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 12), the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10](N)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[I-:21].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([I:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)cc(-c2cccc(F)c2)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: COc1cc(I)cc(-c2cccc(F)c2)c1
Yield: 77.6 %

Procedure:
A similar procedure as described in Example 12, step 5 was used, starting from 3′-fluoro-5-methoxy-biphenyl-3-ylamine (940 mg, 4.32 mmol), sodium nitrite (545 mg, 7.79 mmol), and potassium iodide (1.44 mg, 8.65 mmol) to afford 3′-fluoro-3-iodo-5-methoxy-biphenyl (1.1 g, 78%) as an amorphous light yellow oil: ES(+)-HRMS m/e calculated for C13H10FIO (M+H)+ 329.1190, found 329.1192.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C1C=CC(COC([NH:34][C@H:35]([C:42](O)=[O:43])[CH2:36][C:37]2[NH:41][CH:40]=[N:39][CH:38]=2)=O)=CC=1>>[NH2:34][C@@H:35]([CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)[C:42]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:43]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1cnc[nH]1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method A, and employing ((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-histidine-OH as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 8.16 (s, 1H), 7.19 (s, 1H), 4.15 (t, 1H), 4.12-3.98 (m, 1H), 3.38-3.10 (m, 4H), 1.94 (br.d, 2H), 1.85-1.60 (m, 6H), 1.56 (dd, 2H), 1.40-1.16 (m, 3H), 1.15-0.96 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 41.59. LCMS m/z: [M+H]+=373.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].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>C(OCC)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].C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(OC)nc2)CC1
Temperature: 70 °C

Procedure:
In a round-bottom flask, 20 ml of anhydrous toluene is added and degassed several times from vacuum/N2. 2-methoxy-5-bromopyridine (752 mg, 4.0 mmol), ethyl isonipecotate (740 mg, 4.8 mmol), sodium t-butoxide (537 mg, 5.6 mmol), Pd2(DBA)3 (73 mg, 2 mol %) and of BINAP (100 mg, 0.16 mmol) are added and heated to 70° C. under N2 for 16 hrs. The reaction is cooled to r.t. and taken up in 100 ml of ethyl ether and washed with brine (2×50 ml). The ether is dried over MgSO4, filtered and reduced to an oil under vacuum. The compound is purified by flash chromatography on silica gel using 20% ethyl acetate/hexane as the eluent to provide 6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 1H), 7.28 (dd, 1H), 6.66 (d, 1H), 4.15 (q, 2H), 3.87 (s, 3H), 3.42 (dt, 2H), 2.71 (dt, 2H), 2.39 (m, 1H), 2.03 (m, 2H), 1.90 (m, 2H), 1.26 (t, 3H); MS (EI) 264 (M)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11].C([Li])CCC.[CH3:17][S:18]SC.Cl>C(OCC)C.CCCCCC>[Br:11][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[S:6][C:2]=1[S:18][CH3:17]
Reactant: CSSC
Reactant: Brc1sc2ccccc2c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.76 g of 2,3-dibromobenzo[b]thiophene in 75 ml of diethyl ether was cooled to 0° C. and 19 ml of a 1.6M solution of n-butyl lithium in hexane and 10 ml of diethyl ether were added. A pink slurry formed which was stirred for one hour. A solution of 2.7 ml of methyl disulfide in 10 ml of diethyl ether was added and the reaction mixture was stirred for 4 hours at 0° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was vacuum distilled at 1.5 torr providing 1 g of the desired subtitled intermediate.
Reaction SMILES: [O:1]([C:8]([N:10]([CH:21]([C:23]#[CH:24])[CH3:22])[O:11]C(OC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[OH-].[NH4+:26]>CO>[CH3:22][CH:21]([N:10]([OH:11])[C:8]([NH2:26])=[O:1])[C:23]#[CH:24]
Reactant: [NH4+]
Reactant: C#CC(C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Agent: [OH-]
Solvent: CO
Product: C#CC(C)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 28 %

Procedure:
A mixture of N,O-Bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (3.14 g,9.7 mmol), methanol (20 mL), and ammonium hydroxide (20 mL) was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (2% methanol, methylene chloride) afforded N-(3-butyn-2-yl)N-hydroxyurea (340 rag, 28%). 1H NMR (DMSO-26, 300 MHz) δ1.25 (d, 3H, J=7.5 Hz), 3.05 (d, 1H, J=3.0 Hz), 4.85 (dq, 1H, J=7.5, 3.0 Hz), 6.50 (br s, 1H), 9.25 (S, 1H). MS (DCI/NH3) m/e 129 (M+H)+, 146 (M+NH4)+. Anal calcd for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86. Found: C, 47.03; H, 6.27; N, 21.98.