Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:11][CH:10]=2)O1.[C:23]([O:27][C:28]([N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH:32]=[C:33](OS(C(F)(F)F)(=O)=O)[CH2:34]2)=[O:29])([CH3:26])([CH3:25])[CH3:24].[Cl-].[Li+].C([O-])([O-])=O.[K+].[K+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH:32]=[C:33]([C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:20][CH:21]=1)[CH2:34]2)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)OB(c2ccc(Oc3ccccn3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccc(Oc4ccccn4)cc3)CC1CC2
Yield: 56.6 %

Procedure:
2-[4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]pyridine (0.62 g, 2.1 mmol), 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (0.75 g, 2.1 mmol) (intermediate 1), tetrakis(triphenylphosphine)-palladium (0.24 g, 0.21 mmol) and lithium chloride (0.107 g, 2.52 mmol) are placed in 10 ml of DME and 2.6 ml of a 2N aqueous solution of K2CO3. The reaction medium is refluxed for 16 h. After hydrolysis and extraction with ethyl acetate, the organic phase is dried over MgSO4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in heptane ranging from 0% to 30%. 0.45 g of expected 3-[4-(pyridin-2-yl-oxy)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:32][C@H:33]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[CH:36](OC(=O)C)[O:35][C@@H:34]1[C:46]1[N:47]=[N:48][N:49]([CH2:51][CH3:52])[N:50]=1)(=[O:31])[CH3:30].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:39]([O:38][C@@H:37]1[C@H:33]([O:32][C:29](=[O:31])[CH3:30])[C@@H:34]([C:46]2[N:47]=[N:48][N:49]([CH2:51][CH3:52])[N:50]=2)[O:35][C@H:36]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:41])[CH3:40]
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)(Cl)Cl
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)OC)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A suspension of methyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 29) (0.4 g, 1.07 mmol) in 1,1,1-trichloroethane (25 ml) was treated with N,O-bis(trimethylsilylacetamide) (1.6 ml, 6.54 mmol) and the mixture was heated under reflux for one hour. The solvent was removed under reduced pressure and the residue was twice azeotroped with toluene. The residue was dissolved in toluene (5 ml) and treated sequentially with a solution of (2R,3R,4R)-4,5-bis(acetyloxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO-A-9967265) (0.45 g, 1.31 mmol) in toluene (20 ml) and then trimethylsilyltriflate (0.25 ml, 1.37 mmol). The mixture was heated under reflux for 3 hours and then allowed to stand at room temperature overnight. The solution was diluted with ethyl acetate (40 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine (20 ml), dried (anhydrous magnesium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (80:20 by volume) gradually changing to dichloromethane:ethyl acetate (60:40 by volume) to afford the title compound (0.44 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([N:17]=[N+:18]=[N-:19])[CH2:14][NH:13]1)=[O:11].[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([N:17]=[N+:18]=[N-:19])[CH2:14][N:13]1[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:11]
Reactant: O=CC1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1
Reaction time: 20 h
Yield: 177.7 %

Procedure:
To a solution of (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl ester trifluoro-acetate salt (9.6 g, 33.08 mmol) in 60 mL dichloromethane were added cyclohexanecarbaldehyde (2.6 g, 23.66 mmol), acetic acid (2.5 mL) and sodium triacetoxyborohydride (14.2 g, 66.16 mmol) and the reaction mixture was stirred at room temp. for 20 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated to give (2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (11.2 g, crude) as a light brown liquid. The compound was used in the next step without further purification. MS caled. for C13H23N4O2 [(M+H)+] 267.0, obsd. 267.2.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[H][H].CO>[C].[Pd].O.C(O)C>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]

Procedure:
(viv) 5-(4-Methyl-4-nitropentylidene)hydantoin is reduced with a transition metal catalyst (such as palladium) and the like to give 5-(4-methyl-4-nitropentyl)hydantoin. For example, 5-(4-methyl-4-nitropentylidene)hydantoin is reacted with hydrogen gas upon addition of palladium-carbon (generally 0.1–5 mol %, preferably 0.5–2 mol %) in a mixed solvent of a water soluble solvent, such as methanol, ethanol and the like, and water for 1–12 h, preferably 2–5 h. The reaction solvent is concentrated to dryness to give 5-(4-methyl-4-nitropentyl)hydantoin. The obtained 5-(4-methyl-4-nitropentyl)hydantoin can be isolated and/or purified by a conventional method, such as chromatography and the like, but generally, can be used in the next step without isolation and/or purification.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH:13]([NH:16][C:17]([NH2:19])=[O:18])([CH3:15])[CH3:14].Cl>C(O)C.O>[CH:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)NC(N)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)N1C(=O)CC(=O)NC1=O
Yield: 95.8 %

Procedure:
13.8 g (0.6 mole) of sodium are dissolved in 250 ml of anhydrous ethanol. 61.2 g (0.46 mole) of diethyl malonate and 47.3 g of isopropyl urea (0.46 mole) are added to the resulting solution. The mixture thus formed is heated for 7.5 hours to 120° C. (temperature of the bath). After cooling, a solution of concentrated HCl and water (1:4) is slowly added until the precipitate formed during the reaction has dissolved. The resulting solution is evaporated until a precipitate appears and is then left standing at 0° C. The precipitate is then filtered, washed with cold water and dried, giving 75 g of colourless crystals.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:18][C:19]#[CH:20])[CH2:17][O:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>C(O)CCC>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([OH:16])([CH2:17][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH2:18][C:19]#[CH:20])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: c1nc[nH]n1
Reactant: C#CCC1(c2ccc(Cl)c(Cl)c2)CO1
Agent: [Na]
Solvent: CCCCO
Product: C#CCC(O)(Cn1cncn1)c1ccc(Cl)c(Cl)c1
Yield: 59.3 %

Procedure:
0.275 g (0.011 mol) of sodium is introduced into a boiling solution of 8.05 g (0.116 mol) of 1,2,4-triazole in 400 ml of n-butanol. 24 g (0.105 mol) of 2-(3,4-dichlorophenyl)-2-propargyl-oxirane, dissolved in 50 ml of n-butanol, are then added. The solution is heated at the boil for 12 hours, the solvent is distilled off in vacuo, the residue is taken up in 200 ml of trichloromethane, the solution is washed with twice 50 ml of water, and the organic phase is dried over anhydrous sodium sulphate and then filtered over 200 g of silica gel. 18.45 g (53.6% of theory) of 4-(3,4-dichlorophenyl)-5-(1,2,4-triazol-1-yl)-pent-1-in-4-ol are obtained as colorless crystals of melting point 114° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[C:17]3=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=[C:16]3[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]2=3)[CH2:7][CH2:6]1)=[O:4].CN1CCOCC1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[Br:22][C:20]1[CH:21]=[C:16]2[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]=3[CH:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:6][CH2:7]3)[C:17]2=[N:18][CH:19]=1
Reactant: NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1

Procedure:
The title compound of Example 3 (0.15 g, 0.31 mmol) was dissolved in CH2Cl2 (1.5 mL). 4-Methylmorpholine (102 uL), followed by mesyl chloride (36 uL, 0.47 mmol, 1.5 equiv.) was then added. Reaction mixture was stirred at room tempearture ovemite. The CH2Cl2 phase was washed twice with Sat. NaHCO3, brine and then dried over Na2SO4. CH2Cl2 was then removed by rotary evaporation and resulting residue was purified on silica gel column eluting with 30% EtOAc/CH2Cl2 to give the title compound as a white solid (0.109 9, mp=120-140° C., MH+==562.
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]1[O:20][CH:1]1[CH3:2]
Reactant: COc1cccc(C=O)c1
Reactant: c1ccc([SH+]c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 3-methoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:35])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:35][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(di flu oromethyl)phenyl)-2-methoxybenzamide (Intermediate-39, 0.050 g, 0.10 mmol), cyclopropane carbonyl chloride (0.016 g, 0.15 mmol), DIPEA (2.0 mL) and THF (2 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.7 Hz, 4H), 1.60 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=5.4 Hz, 2H), 7.05 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.41-7.55 (m, 4H), 7.65 (d, J=9.0 Hz, 1H), 7.74 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.07 (s, 1H), 8.72 (m, 1H), 10.33 (s, 1H); MS (m/z): 566.29 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([C@@H:8]1[C@@H:9]([O:27][CH2:28][CH2:29][CH2:30][OH:31])[C@H:10]([CH3:26])[O:11][C:12](=[O:25])[C@@H:13]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][O:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)propanoic acid (162 mg, 0.359 mmol, 1.00 equiv) in THF (3.6 mL, 0.1 M) at 0° C. (ice water bath) was added a 1 M solution of borane tetrahydrofuran complex in THF (0.897 mL, 0.897 mmol, 2.5 equiv). The resulting colorless solution was stirred at 0° C. for 4 h, quenched with 1 N HCl (3 mL), poured into H2O (20 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to provide a film. The crude film was purified by automated silica gel column chromatography (5-75% acetone in hexanes) to yield tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-hydroxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (121 mg, 77%) as an oily white solid: IR (ATR) 3365, 2927, 2874, 1747, 1695, 1496, 1454, 1367, 1295, 1202, 1071, 853, 746 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.12 (m, 5H), 5.17 (d, J=8.3 Hz, 1H), 4.98 (dq, J=8.6, 6.4 Hz, 1H), 4.60 (q, J=7.5 Hz, 1H), 3.96-3.83 (m, 2H), 3.83-3.75 (m, 2H), 3.71 (dt, J=8.8, 5.8 Hz, 1H), 3.49-3.37 (m, 2H), 3.26 (dd, J=11.4, 7.4 Hz, 1H), 3.16 (t, J=8.7 Hz, 1H), 3.09 (dd, J=13.6, 3.5 Hz, 1H), 2.38 (t, J=12.5 Hz, 1H), 2.13 (d, J=13.0 Hz, 1H), 1.91 (d, J=16.2 Hz, 1H), 1.86 (p, J=5.8 Hz, 2H), 1.50 (d, J=6.4 Hz, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.27, 154.99, 139.66, 129.13, 128.49, 126.22, 99.99, 85.31, 80.12, 77.22, 75.10, 72.86, 72.11, 71.09, 61.25, 52.89, 47.30, 35.14, 32.59, 28.27, 18.76; HRMS-ESI (m/z) [M+Na]+ calc'd for C23H35NO7Na, 460.2306. found, 460.2320.
Reaction SMILES: [O:1]([CH:9]([C:36]([F:41])([F:40])[CH2:37][CH2:38][CH3:39])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:41][C:36]([F:40])([CH2:37][CH2:38][CH3:39])[CH:9]([OH:1])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1

Procedure:
To a solution of methyl (Z)-7-[(1 R)-(2 R,3 R,5 S)-2-{4 (RS)-t-butyldimethylsiloxy-5,5-difluorooctyl}-5-hydroxy-3-tetrahydropyranyloxycyclopentyl]hept-5-enoate (17) (1.90 g) in tetrahydrofuran was added tetrabutylammonium fluoride in tetrahydrofuran (1.0M, 15.7 ml). The resultant mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silicagel column chromatography to give the titled compound (18).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([NH:26][C:27]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 2-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 0.5 g, 2.22 mmol) in 20 mL of THF was cooled to 0° C. (ice/water bath). Benzoyl isothiocyanate was added dropwise over a period of 10 min. The mixture was warmed to room temperature and stirred for 20 hr. The solvent was evaporated and the yellow solid washed with 50 mL of 1:1 ethyl acetate/hexanes solution (yield 0.736 g, 85%). H1 NMR (DMSO d6) δ: 12.43 (s, 1H), 11.53 (s, 1H), 9.92 (s, 1H), 8.00-7.95 (m, 3H), 7.06-6.96 (m, 6H), MS (ES): MH+ 389.1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:33].[OH-]>O1CCOCC1>[NH2:33][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(-c2cccc(C(=O)c3cn(C4CCCC4)c4ncnc(Cl)c34)c2)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cccc(C(=O)c3cn(C4CCCC4)c4ncnc(N)c34)c2)cc1
Yield: 74 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4′-dimethylamino-biphenyl-3-yl)-methanone ((40 mg, 0.089 mmol) and NH4OH (2 mL) in 1,4-dioxane (2 mL) was heated to 50° C. in a sealed tube. After 12 h the reaction was concentrated under reduced pressure and purified by flash column chromatography (CH2Cl2/MeOH 95:5) to afford the title compound as a yellow solid (28 mg, 74%). MS: 426.0 (MH+); HPLC Rf: 7.38 min. (HPLC method 4).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([CH2:20][C:21]([O:23]CC)=[O:22])(=O)[CH:16]([CH3:18])[CH3:17].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([CH:16]([CH3:18])[CH3:17])=[C:20]([C:21]([OH:23])=[O:22])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C(C)C)cc1
Temperature: 50 °C
Reaction time: 63 h
Yield: 93.4 %

Procedure:
4-Azido-N-ethylbenzamide (0.94 g, 4.70 mmol) and ethyl isobutyrylacetate (1.03 g, 6.10 mmol, 1.3 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (461 mg, 6.10 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 50° C. for 63 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (20 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 50 ml). The aqueous layer was acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-brown powder (1.33 g, 4.39 mmol, 93.4%).
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7]([NH:10]C([C@H](N)C3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N.OS(O)(=O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.CCN1C2N=C(C)C=CC=2C(=O)C(C(O)=O)=C1.C(O)C(N)(CO)CO.CCCCCCCCCCCCOS([O-])(=O)=O.[Na+].SCCO.SC[C@H]([C@@H](CS)O)O>OCC(CO)O>[CH2:7]([NH2:10])[C:8]([NH:4][CH2:3][C:21]([OH:23])=[O:22])=[O:9]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Solvent: OCC(O)CO
Product: NCC(=O)NCC(=O)O
Temperature: 37 °C
Reaction time: 0.33 h

Procedure:
[3H]Fatty acid labeling of PK-A C-subunit produced in E. coli. Four ml cultures of the double transformants were shaken at 37° C. to an OD600 of 0.5 in LB broth+100 μg/ml ampicillin and 100 μg/ml kanamycin sulfate. Isopropyl-β-D-thiogalactopyranoside (IPTG) was then added to a final concentration of 1 mM to induce NMT production (see Results, below). When the cultures reached OD600 =1.0 (approximately 40 min later), nalidixic acid was added to a final concentration of 50 μg/ml to induce C-subunit production (see Results, below). [3H]Myristate (New England Nuclear; 39.3 Ci/mmol, 113 μCi added per ml of culture), [3H]palmitate (New England Nuclear; 30 Ci/mmol, 143 μCi/ml), or [3H]10-(propoxy)decanoate [Heuckeroth and Gordon, Proc. Natl. Acad. Sci. USA 86, 5262-5266 (1989)] (31.7 Ci/mmol, 800 μCi/ml) was added simultaneously with the nalidixic acid. Cultures were shaken for an additional 20 min at 37° C. and the cells were harvested by centrifugation. Lysates were prepared by boiling E. coli contained in the pellet for 10 min in 40 μL of a solution of 125 mM Tris, pH 8.0, 4% SDS, 20% glycerol, 10% β-mercaptoethanol, and 0.2M dithiothreitol. Cell debris was removed by centrifugation and 15 μl aliquots of the supernatant were subjected to SDS-PAGE [Laemmli, Nature 227, 680-685 (1970)] and subsequent fluorography using EN3HANCE (New England Nuclear) autoradiography enhancer. For Western blot analyses, 50 μg of reduced and denatured lysate proteins, prepared from unlabeled E. coli producing Gly2 -C-subunit or Ala2 -C-subunit, were separated by SDS-PAGE, electroblotted onto nitrocellulose [Burnette, Anal. Biochem. 112, 195-230 (1981)], and the filters probed with polyclonal, monospecific rabbit antisera raised against purified mouse C-subunit. Antigen-antibody complexes were visualized with 125I-protein A [Burnette, supra⟧
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Cl:20])[CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(C(=O)Nc2ccc(Cl)cc2)c1N
Product: Cc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-chlorophenyl)-2-amino-3-methylbenzamide (0.40 g, 1.5 mmol) in chloroform (3 mL) at 0° C. was added SO2Cl2 (0.3 g, 2.3 mmol). The mixture was warmed to ambient temperature and stirred for 1 hour. Concentration of all volatiles in vacuo afforded N-(4-chlorophenyl)-2-amino-3-methyl-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6) 10.2 (s, 1), 7.8 (d, 2), 7.6 (s, 1), 7.4 (d, 2), 7.2 (s, 1), 6.2 (br, 2), 2.1 (s, 3) ppm.