Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.C1COCC1.Br[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1.[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH:30]=[O:31])[CH2:28][C@@H:27]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:26]1)=[O:24])[CH:20]=[CH2:21].[Cl-].[NH4+]>C1COCC1>[CH2:19]([O:22][C:23]([N:25]1[CH:29]([CH:30]([OH:31])[C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[CH:13][N:12]=2)[CH2:28][CH:27]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Brc1ncc2sccn12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(O)c1ncc2sccn12
Temperature: -3 °C
Reaction time: 0.08 h

Procedure:
A 0.99 M ethylmagnesium bromide/THF solution (15.2 ml) is diluted with 60 ml of anhydrous THF. A solution of 3.046 g of 5-bromoimidazo[5,1-b]thiazole in 60 ml of anhydrous THF is added dropwise to the diluted solution in an argon atmosphere over a period of 15 min (4 to 8° C.), and the mixture is stirred in this state for 5 min. The mixture is then cooled to −3° C. over a period of 10 min. Thereafter, a solution of 4.702 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 60 ml of anhydrous THF is added dropwise thereto over a period of 20 min (−3 to −1° C.). The mixture is stirred in this state at −1 to +1° C. for 80 min. An aqueous semi-saturated ammonium chloride solution (180 ml) is added thereto, and the mixture is extracted twice with 360 ml of ethyl acetate. The organic layer is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure to give a yellow oil which is then purified by flash column chromatography on silica gel (n-hexane:ethyl acetate=1:1 to 1:2) to give 4.934 g of 3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine (stereoisomer A, a high polar component) as a colorless amorphous material and 605.5 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidine(stereoisomer B, a low polar component) as a slightly yellow, high viscous material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16](Cl)[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)ccc1Oc1cccnc1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a stirred solution of the product from Example 1 (101 mg, 0.344 mmol) in MeOH (4 mL) was added a catalytic amount of palladium on carbon. The flask was evacuated of air and placed under a balloon of hydrogen gas. After 1 hr, the mixture was filtered through Celite® and the filtrate was evaporated to provide 85 mg of the title compound (96%).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:15]2([OH:23])[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A suspension of anhydrous cerium chloride (43.9 g, 178.0 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. 4-Fluorophenylmagnesium bromide (75.6 mL of 2.0 M solution in diethyl ether, 151.2 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (15.36 g, 116.4 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature over-night (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Unreacted 2-indanone was distilled off. The residue was subjected to Kugelrohr distillation (165° C./0.3 mm Hg). 2-(4-Fluorophenyl)-2-indanol (21.62 g) was obtained in pure form. 1H-N.M.R. (CDCl3) d 2.22 (br s, 1H), d 3.24 (d, J=16.3 Hz, 2H), d 3.47 (d, J=16.3 Hz, 2H), d 7.04 (m, 2H), d 7.20-7.28(m, 4H), d 7.52(br d, J=9.0, 5.3 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10]C(=O)C(F)(F)F)=[O:6])[CH2:3][OH:4].ClCC(O)=O.[N:25]([O-])=O.[Na+]>O>[N+:1](=[C:2]([CH2:3][OH:4])[C:5]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH2:10])=[O:6])=[N-:25]
Reactant: O=N[O-]
Reactant: N[C@@H](CO)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=C(CO)C(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
To a solution of O-(L-serinyl)-N-trifluoroacetyl-L-serine (400 mg) and 4M aqueous chloroacetic acid (50 μl) is water (4 ml) was added sodium nitrite (193 mg) at room temperature. After stirring for 15 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and then Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (60 mg) was added. The mixture was stirred for 5 hours at room temperature, and chromatographed on carbon (50 ml) eluting successively with water and a 9:1 mixture of water and acetone to give a crude product, which was chromatographed on silica gel eluting with a mixture of methylene chloride, methanol and water (10:6:1 to 5:3:1), and also chromatographed on silica gel eluting with a 5:3:1 mixture of methylene chloride, methanol and water (5:3:1) to give a pure product which was lyophylized to give O-(2-diazo-3-hydroxy-1-oxopropyl)-L-serine (33 mg).
Reaction SMILES: C([Si](C=C)(C)O[Si](C)(C)C)=C.C([Si](C=C)(OCC)O[Si](OCC)(OCC)OCC)=C.C[SiH](C)O[Si](O[SiH](C)C)(O[SiH](C)C)O[SiH](C)C.C([C:50]1[C:51]2[C:56]([CH:57]=[C:58]3[C:63]=1[CH:62]=[CH:61][CH:60]=[CH:59]3)=[CH:55][CH:54]=[CH:53][CH:52]=2)=C>C1(C)C=CC=CC=1>[CH:52]1[C:51]2[C:56](=[CH:57][C:58]3[C:63]([CH:50]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:55]=[CH:54][CH:53]=1
Reactant: C=Cc1c2ccccc2cc2ccccc12
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Agent: C=C[Si](C=C)(OCC)O[Si](OCC)(OCC)OCC
Agent: C[SiH](C)O[Si](O[SiH](C)C)(O[SiH](C)C)O[SiH](C)C
Solvent: Cc1ccccc1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 25 °C

Procedure:
To a 100-mL three-necked round bottom flask fitted with a condenser/nitrogen inlet and two stoppers was added divinyltetramethyldisiloxane (4.43 g, 23.8 mmole), divinyltetraethoxydisiloxane (0.38 g, 1.24 mmoles), and tetrakis(dimethylsiloxy)silane (12.33 g, 37.5 mmoles). A solution of 9-vinylanthracene (0.0442 g, 0.525 mmole) in toluene (20 mL) was then added and the mixture stirred at RT. Karstedt's catalyst (21 microliters) was added using an automatic pipette. The mixture was stirred for 1 h then the flask was immersed in an oil bath which was heated to 50° C. overnight. The reaction mixture was cooled then transferred to a single necked round bottom flask and solvent removed on a rotary evaporator. The residue was washed with acetonitrile (4×30 mL), devolatilized using a rotary evaporator at 30° C., followed by devolatization using a Kugelrohr distillation apparatus at 80° C. at full vacuum for 30 mins. The resultant material was a water-white clear liquid (12.85 g, ˜75%). A sample was diluted in methylene chloride and analyzed by UV-Vis spectroscopy. Bands indicative of anthracene were present indicating that the 9-vinylanthracene was incorporated into the polymer.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:20]([CH3:22])[CH3:21])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15])[C:7]2=[O:12].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@H:30]([CH3:34])[C:31]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:20]([CH3:22])[CH3:21])[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])[C:7]3=[O:12])=[O:32])=[CH:28][CH:29]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](C(=O)NC1CC1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NC1CC1)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-N-cyclopropyl-3-methylbutanamide (0.2 g, 0.0007 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.56 g, 0.0015 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane), and then prep. HPLC gave a white solid. 1H NMR δ (CDCl3) δ: 8.22 (d, J=8.0 Hz, 1H), 8.00 (t, J=7.4 Hz, 1H), 7.52-7.37 (m, 6H), 7.14 (br, 1H), 6.35 (br, 1H), 6.06-6.03 (m, 1H), 5.01 (d, J=11.3 Hz, 1H), 3.82 (q, J=7.2 Hz, 1H), 2.65-2.61 (m, 1H), 2.52-2.32 (m, 1H), 1.64 (d, J=11.1 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.90-0.67 (m 5H) 0.51-0.41 (m, 2H). MS m/z 465.8 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:9][CH2:8][C:7]2[C:12]3[C:13](=[C:9]([CH3:10])[CH:8]=[CH:10][CH:11]=3)[CH:14]=[CH:15][C:6]=2[C:4]([C:3]2[CH:2]=[CH:1][C:7]3[C:6](=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:11])[C:4]=2[CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: CC=CC(=O)c1cccc2ccccc12
Product: Cc1cccc2c(CCN3CCCCC3)c(C(=O)c3ccc4c(C)cccc4c3CCN3CCCCC3)ccc12

Procedure:
5-methylacryloylnaphthalene (21.8 mg) and piperidine (9.1 mg) were reacted at 50° C. for 5 hours.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:5][CH:4]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4.0M hydrogen chloride in 1,4-dioxane (2.508 mL) was added to a solution of tert-butyl (S)-2-(5-chlorothiophen-2-yl)-3-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylisopropylcarbamate (283 mg, 0.502 mmol) in 1,4-dioxane (2.5 mL) and methylene chloride (2.5 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 1 hour. The mixture was concentrated in vacuo. The residue was then dissolved in a minimum volume of DCM (1 mL) and added dropwise to ether (10 mL) at 0° C. with stirring. A white solid precipitated. The solvents were evaporated with a rotovap in a 25° C. bath. The off-white solid was dried under high vacuum overnight to give (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (537 mg, 99.9%). MS (APCI+) [M+H] +464.1. 1H NMR (D20, 400 MHz) δ 8.53 (s, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 5.40 (t, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.31-4.27 (m, 1H), 4.09-3.97 (m, 2H), 3.84-3.42 (m, 10H), 2.36-2.30 (m, 1H), 2.21-2.13 (M, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20](=[O:22])[CH3:21])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Compound 186 (300 mg, 1.11 mmol) was dissolved in pyridine (3.7 mL), and acetyl chloride (0.130 mL, 1.89 mmol) and N,N-dimethylaminopyridine (6.75 mg, 0.0553 mmol) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=2:1) to afford the entitled Compound 188 (233 mg, 67%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[N:14]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:20]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:22])=[O:21])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(COCC2CC2)cn1
Reactant: O=S(=O)(Cl)N1CCCCC1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)N1CCCCC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.089 g) and piperidine-1-sulfonyl chloride (0.142 g) as a light yellow gum (0.027 g). MS (ESI−): 324.2 ([M−H]−)
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CO.C(C(C)=O)C.ClC1C=CC=CC=1Cl.CCOCC>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][C:2]([CH3:6])([CH3:5])[CH:3]=[CH:4][C:25]=3[CH:24]=2)=[CH:30][CH:31]=1
Reactant: C#CC(C)(C)Cl
Reactant: COc1ccc(CSc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: CCC(C)=O
Solvent: CO
Product: COc1ccc(CSc2ccc3c(c2)C=CC(C)(C)O3)cc1

Procedure:
A solution of 73.84 g of 3-chloro-3-methyl-1-butyne in 225 ml of methanol, 11.95 g of potassium iodide and 99.50 g of potassium carbonate was added to the whole of the 4-(4-methoxybenzylthio)phenol prepared as described in step (a) above in 0.9 liters of methyl ethyl ketone, and the resulting mixture was heated under reflux for 40 hours in an atmosphere of nitrogen. At the end of this time, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to afford 67.68 g of an ether as an oil. A solution of the whole of this ether in 340 ml of o-dichlorobenzene was then heated under reflux for 2 hours in an atmosphere of nitrogen. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of cyclohexane and ethyl acetate as the eluent. The eluted product was recrystallized from hexane to afford 48.74 g of the title compound, melting at 58°-59° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([F:23])=[CH:25][CH:26]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)c1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol (0.30 g, 0.944 mmol) in N,N-dimethylformamide (5 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.189 g, 0.99 mmol) and 1-hydroxybenzotriazole monohydrate (0.152 g, 0.99 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.190 g, 0.99 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, 0:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.245 g, 53%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]([OH:33])=O)[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:43]1[C:42]([NH:41][C:31]([C:29]2[CH:30]=[C:17]3[NH:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][CH:11]=4)=[C:20]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[C:19](=[O:27])[N:18]3[N:28]=2)=[O:33])=[N:46][N:45]=[N:44]1
Reactant: O=C(O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Reactant: Nc1nnn[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 25 °C
Reaction time: 41 h
Yield: 35.5 %

Procedure:
To a solution of 71 mg (0.16 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid in 4 mL of dimethylformamide (DMF) was added 0.053 mL (0.48 mmol) of 4-methyl-morpholine, 14 mg (0.164 mmol) of 5-aminotetrazole, followed by 100 mg (0.192 mmol) of PYBOP when the solution turned yellow, and the resulting mixture was stirred at rt for 41 h. The reaction mixture was concentrated to give a residue which was purified via reverse-phase chromatography to afford 29 mg (35% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1H-tetrazol-5-yl)-amide (540) as a solid as indicated by 1H-NMR; LC-MS calcd. for C27H26N8O3 [M++H]+: 511.21; found: 511.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[CH3:8].[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[N:6]=[CH:5][C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:2]=1[CH:22]=[CH2:23]
Reactant: Cc1ncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Temperature: 25 °C
Yield: 59.6 %

Procedure:
5-Bromo-6-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.95 g, 2.7 mmol, Step 34a above) was treated with vinyl tributyltin (1.62 mL, 5.56 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.29 g, 0.25 mmol) in toluene (30 mL) at 90° C. overnight. The reaction was cooled to ambient temperature and chromatographed on silica gel with 2:1 hexane-EtOAc eluent to provide 6-methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.49 g, 60%): MS (CI/NH3) m/z: 305 (M+H)+ ; 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 2.22-2.38 (m, 2H), 2.52 (s, 3H), 3.91 (dt, J=2, 6 Hz, 2H), 4.13 (dd, J=3, 10 Hz, 1H), 4.30-4.36 (m, 1H), 4.49-4.55 (m, 1H), 5.40 (dd, J=1, 11 Hz, 1H), 5.64 (dd, J=1, 17 Hz, 1H), 6.84 (dd, J=11, 17 Hz, 1H), 7.32 (d, J=3 Hz, 1H), 8.13 (d, J=3 Hz, 1H). The product from above (0.47 g,1.53 mmol) was treated with 8 mL of 1:1 TFA-methylene chloride at 0° C. for 2 hours. The volatile components were evaporated in vacuo, and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with CH2Cl2. The combined organic layers were washed with water and dried over MgSO4 to provide the product (277 mg, 89% yield). Half of the sample was dissolved in ether and treated with 1 M HCl in ether to provide 85 mg of the title compound as an off-white solid: mp 154-155° C.; [α]D -8.9 (c 0.45, MeOH); 1H NMR (CD3OD) δ 2.63-2.77 (m, 2H), 2.74 (s, 3H), 4.08-4.16 (m, 2H), 4.52-4.64 (m, 2H), 4.85-4.95 (m, 1H), 5.80 (d, J=11 Hz, 1H), 6.15 (d, J=17 Hz, 1H), 7.02 (dd, J=11, 17 Hz, 1H), 8.36 (d, J=2 Hz), 1H, 8.48 (d, J=2 Hz, 1H); MS (CI/NH3) m/z; 205 (M+H)+ ; Anal. Calcd for C12H16N2O.2.1 HCl: C, 51.32; H, 6.50; N, 9.97. Found: C, 51.60; H, 6.21; N, 9.82.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[C:12]3[C:13]([NH:15][C:16](=[O:17])[C:11]=23)=[O:14])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Solvent: CC#N
Product: O=C1NC(=O)c2c(CCCCCCCCN3CCOCC3)cccc21

Procedure:
8-Bromooctylphthalimide (676 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous acetonitrile (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.Cl>C1COCC1>[CH2:16]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 500 mg (1.6 mmol, 1 equiv.) of 4-dibenzylamino-butyric acid ethyl ester in 1 ml of THF was added 4 ml of HCl 2N and the resulting mixture was stirred for 48 hours. After decantation and separation, the aqueous layer was extracted twice by ethyl acetate. The pH was fixed to 5 using solid sodium carbonate and the aqueous layer was extracted by dichloromethane. The dichloromethane layer was dried over sodium sulphate, evaporated and used without further purification.