Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]3[N:11]=[C:12]([O:19][CH2:20][C:21](F)(F)F)[C:13]4[C:18]([C:9]3=[N:8][N:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:2]1.[CH3:25][N:26]([CH3:36])[CH2:27][CH2:28][N:29]1C(CO)=[N:32][CH:31]=[N:30]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]3[N:11]=[C:12]([O:19][CH2:20][C:21]4[N:29]([CH2:28][CH2:27][N:26]([CH3:36])[CH3:25])[N:30]=[CH:31][N:32]=4)[C:13]4[C:18]([C:9]3=[N:8][N:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:2]1
Reactant: FC(F)(F)COc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: CN(C)CCn1ncnc1CO
Product: CN(C)CCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The reaction was carried out using the procedure described in Example 1, Step 4, using 3-isoxazol-3-yl-6-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[3,4-α]phthalazine (WO-A-9850385) (100 mg, 0.29 mmol) instead of 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine with [2-(2-dimethylaminoethyl)-2H-[1,2,4]triazol-3-yl]methanol (Example 4, Step 2) (51 mg, 0.29 mmol). Crude residue was purified on silica eluting 2-6% MeOH/DCM, followed by crashing out from DCM using isohexane. The title compound was isolated by filtration to give a cream solid (47 mg, 39%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.B.C1COCC1.O>FC(F)(F)C(O)=O.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH2:11][NH2:12])[CH2:2]1
Reactant: NCCc1c[nH]c2ccccc12
Agent: B
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCCC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
2-(3-Indolyl)ethylamine in an amount of 9.4 grams (58.8 millimoles) was dissolved in 120 milliliters of trifluoroacetic acid under nitrogen. The solution was cooled in an ice bath and 100 milliliters of about 1 M BH3.THF in tetrahydrofuran solution was added slowly over about 30 minutes. Thereafter, water (50 milliliters) was added, the resulting solution stirred at room temperature for about 75 minutes, and then evaporated in vacuo to about 40 milliliters of a semi-solid viscous oil. The oil was partitioned between methylene chloride and aqueous sodium hydroxide solution (pH>10). The organic layer was dried over potassium carbonate, filtered and evaporated in vacuo to obtain 8.6 grams of a yellow oily 2-(3-indolinyl)ethylamine product of 98 percent purity (by gas layer chromatographic analysis) in a 90 percent isolated yield. NMR was appropriate for the compound. The HCl salt of 2-(3-indolinyl)ethylamine had a melting point of 186°-188° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC(O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (11.64 mmoles) is charged into a 100 mL 3-necked round bottomed flask followed by addition of 2-propanol (16 mL, 3.72 volumes). The yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (3.3 g, 37.84 mmoles) is added over 2-5 minutes. Contents are refluxed for 6 hr. The slurry is cooled to 25° C. 2-Propanol (32 mL, 7.44 volumes) and water (8.6 mL, 2.0 volumes) are added and the mixture warmed to 70-75° C., filtered and concentrated to ˜9 volumes at atmospheric pressure. The clear solution is gradually cooled to 55° C., seeded with 0.06 g of crystalline 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 0.5 mL 2-propanol, rinsed with additional 0.5 mL 2-propanol and added to crystallization flask. The slurry is cooled to 0-5° C., maintained for 1 hr., filtered and the product rinsed with 2-propanol (9 mL, 2.1 volumes). Suctioned dried under vacuum at 60° C. to afford 4.6 g of dry 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (88.8% yield, purity by HPLC assay is 99.88%). MS (ES)=420 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:21]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(Nc1nc2c(Br)cccn2n1)c1ccccc1
Product: O=C(Nc1nc2c(-c3ccoc3)cccn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 56 but starting from N-(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B9), 159 mg; 0.50 mmol; 1.0 eq.) and furan-3-boronic acid (112 mg; 1.0 mmol; 2.0 eq.) as a white powder (80 mg, 52%). HPLC, Rt: 3.26 min. (purity 99.6%). LC/MS, M+(ESI): 305.0, M−(ESI): 303.1.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[CH:24]=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:15]2[N:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[CH:24]=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c(N2CCCNCC2)n(-c2ccccc2)c2ccccc12
Yield: 86 %

Procedure:
4-(3-Formyl-1-phenyl-1H-indole-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.06 g, 2.53 mmol) and trifluoroacetic acid (10 mL) in dichloromethane (4 mL) is stirred overnight at room temperature. The solvent is evaporated off and the residue dissolved in dichloromethane (10 mL), washed with 5% aq sodium carbonate, with water, with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane-5 to 10% methanol. Product containing fraction are combined and concentrated to afford 2-[1,4]diazepan-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (86% yield) as a white solid. LC/MS: MS 320 (M+H); 2.5 min; NMR (CDCl3) 10.30 (1H, s), 8.25 (1H, d), 7.03-7.70 (7H, m), 6.97 (1H, d), 3.20-3.46 (4H, m), 2.84 (4H, m) 1.62(2H, m).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccccc2)c2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.0 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of dibenzylamine (11.8 g, 0.06 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 0° C. The reaction mixture was allowed to cool to -76° C., after which time the reaction mixture was stirred for 0.25 hours. The solid carbon dioxide-acetone bath was then removed and the reaction mixture was stirred for an additional 2 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried and concentrated in vacuo to yield an orange glass. The orange glass was distilled at 220° C. and 0.25 torr and the resulting solid residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was crystallized from diethyl ether and petroleum ether to yield 1-phenyl-2-(phenylmethyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.15 g, 32% yield) as a white solid having a melting point of 99°-101° C. and the following analysis:
Reaction SMILES: [CH2:1]([C:8]([OH:19])([C:16]([OH:18])=[O:17])[CH2:9][C:10](=[N:14]O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].N[C@H](C[C@@](CC1C=CC=CC=1)(O)C(O)=O)C(O)=O.N[C@@H](C[C@@](CC1C=CC=CC=1)(O)C(O)=O)C(O)=O>CO.N.[C].[Pd]>[NH2:14][CH:10]([CH2:9][C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:19])[C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(CC(O)(Cc1ccccc1)C(=O)O)=NO
Reactant: [H][H]
Agent: [Pd]
Agent: N
Agent: N[C@@H](C[C@](O)(Cc1ccccc1)C(=O)O)C(=O)O
Solvent: CO
Product: NC(CC(O)(Cc1ccccc1)C(=O)O)C(=O)O

Procedure:
0.25 g (0.94 mmol) of 4-benzyl-4-hydroxy-2-hydroxyiminoglutaric acid was dissolved in 10 ml of aqueous 50% methanol solution, to which 0.5 ml of aqueous 28% ammonia was added. 1.0 g of 5% palladium-carbon (50% hydrous product) was added, for reaction at ambient temperature and a hydrogen pressure of 7.7 atmospheres. 72 hours later, the catalyst was filtered off, and the reaction solution was concentrated to dryness, to obtain 0. 10 g (0.35 mmol) of the ammonium salt of (2S, 4S)/(2R, 4R)-2-amino-4-benzyl-4-hydroxyglutaric acid and 0.10 g (0.35 mmol) of the ammonium salt of (2R, 4S)/(2S, 4R)-2-amino-4-benzyl-4-hydroxyglutaric acid as a mixture.
Reaction SMILES: [ClH:1].Cl.[NH:3]=[C:4]1[NH:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[H][H]>CCO.[Rh]>[ClH:1].[ClH:1].[NH:3]=[C:4]1[NH:10][CH:9]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N=C1CCCCC(Cc2ccc(N)cc2)N1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CC2CCC(N)CC2)N1
Yield: 168.8 %

Procedure:
The product of Example 274 (0.31 g, 1.2 mmol) in 30 mL of EtOH was reduced with Rhodium on carbon under 60 psi of hydrogen at 60° C. Solvent removal in vacuo followed by lyophilization in water gave 0.3 g of the title material.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:36]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[O:43])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Agent: Cl
Product: CCCCCC(CC(=O)Nc1cc(CNC(=O)c2ccncc2)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 72B) and isonicotinoyl chloride hydrochloride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)(=O)C.O>[I:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(I)cc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc2cc(I)ccc2c(=O)[nH]1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-4-iodobenzamide (1.0 g, 3.61 mmol) in glacial acetic acid (10 mL) at rt was added diethyl oxalate (5 mL). The mixture was heated at 120° C. for 24 h. The mixture was cooled to rt and diluted with H2O until a precipitate formed. The precipitate was removed by filtration, washed with H2O, and dried under high vacuum for several hours to afford ethyl 7-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.0 g, 76%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, 3H), 4.48 (q, 2H), 7.90 (d, 1H), 7.95 (d, 1H), 8.20 (d, 1H), 8.28 (s, 1H), 12.78 (s, 1H); LC-MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Yield: 86.5 %

Procedure:
2′, 5′-Dihydroxyacetophenone (II-1) (15.22 g, 0.100 mol), benzyl bromide (17.96 g, 0.105 mol) and potassium carbonate (14.51 g, 0.105 mol) in acetone (200 ml) were refluxed for 16 h. After the solvent was removed under reduced pressure, water was added and the residue was extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was purified by chromatography on silica gel (500 g) eluting with ethyl acetate/hexane=1:4 to give compound (II-2) as yellow crystals (20.96 g, 87%) accompanied by a small amount of di-benzyl derivative. The products were used without further purification. NMR(CDCl3): 2.57(3H, s), 5.04(2H, s), 6.92(1H, d, J=8.8), 7.14-7.31(2H, m), 7.34-7.45(5H, m)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)([O-:3])=[O:2].Cl[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>COCCOC.O.C1C=CC([P]([Pd]([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)=CC=1>[F:32][C:30]1[CH:29]=[CH:28][N:27]=[C:26]([C:5]2[CH:6]=[C:7]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:31]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(F)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
Into a 500-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (15 g, 45.18 mmol, 1.00 equiv) in DME/H2O (100/5 mL), 2-chloro-4-fluoropyridine (7.80 g, 60.00 mmol, 1.20 equiv), K3PO4 (31 g, 146.23 mmol, 3.00 equiv), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (2.00 g, 4.88 mmol, 0.10 equiv), and Pd(PPh3)4 (2800 mg, 2.42 mmol, 0.05 equiv). The resulting solution was stirred for 1 overnight at 80° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of H2O, extracted with 3×300 mL of dichloromethane, and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (10:1). The product was obtained as 8 g of a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30].C(N(CC)CC)C.O1CCCC1>CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:25][C:24]=1[F:30]
Reactant: COC(=O)c1ccc(I)cc1F
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 44, 0.03 g, 0.11 mmol), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.025 g, 0.09 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol) followed by preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a white solid (0.019 g, 40%).
Reaction SMILES: [Li].C(N)CN.[CH3:6][CH:7]([C:9]12[CH2:15][CH:14]1[C:12](=[CH2:13])[CH2:11][CH2:10]2)[CH3:8].CC([C@@]12C[C@@H]1C(=C)CC2)C>>[CH3:13][C:12]1[CH:14]2[CH2:15][C:9]2([CH:7]([CH3:8])[CH3:6])[CH2:10][CH:11]=1
Reactant: C=C1CCC2(C(C)C)CC12
Agent: C=C1CC[C@]2(C(C)C)C[C@H]12
Agent: [Li]
Solvent: NCCN
Product: CC1=CCC2(C(C)C)CC12
Yield: 69.3 %

Procedure:
0.48 g (69 millimoles) of lithium and 9 g (150 millimoles) of ethylenediamine were reacted in the atmosphere of air at a temperature of 128°-133° C. for 4 hours, and then mixed with 82 g of the above-prepared sabinene oil containing 35.7 g (262 millimoles) of (+)-sabinene. The mixture was allowed to react for 6 hours at 130° C. The reaction mixture was treated as described in Example 1 and thereafter, subjected to distillation at 60°-75° C. and 30 mmHg, affording 56.8 g of α-thujene oil containing 47.8% of (-)-α-thujene. The yield of (-)-α-thujene was 76.0%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:45])[CH:19]=[CH:20][CH:21]([NH:37]C(OC(C)(C)C)=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:45])[CH2:19][CH2:20][CH:21]([NH:37][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH3:16]
Reactant: CCOC(=O)C=CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)CCCCCc1ccccc1
Product: CCOC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCc1ccccc1

Procedure:
From 6-phenylhexanoic acid 71a and (RS)-5-(4-Benzyloxy-phenyl)-4-tertbutoxycarbonylamino-pent-2-enoic acid ethyl ester 77 (83% yield): 1H nmr (CDCl3) δ 1.26 (t, J=7.2 Hz, 3H), 1.28-1.90 (m, 9H), 2.11 (t, J=7.4 Hz, 2H), 2.29-2.38 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.71-2.77 (m, 2H), 4.12 (q, J=7.1 Hz, 2H), 5.03 (s, 2H), 5.55 (br d, J=8.7 Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 7.16-7.44 (m, 10H). 13C nmr (CDCl3) δ 173.8, 172.8, 157.5, 142.4, 136.9, 130.3, 129.9, 128.5, 128.3, 128.2, 127.8, 127.4, 125.6, 114.7, 69.9, 60.5, 50.1, 40.3, 36.7, 35.6, 31.1, 31.0, 28.7, 28.6, 25.5, 14.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH:33]=[CH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.C([OH:46])C.[OH-].[Na+].OO>C1COCC1.[Cl-].[Na+].O.CCOCC>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][OH:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCO
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1O[C@@H](CCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-1-propene (10.4 g, 22.68 mmol) in THF (100 mL) at 0° C. was added slowly 9-BBN (58.5 mL, 29.3 mmol, 0.5 M in THF). The mixture was allowed to warm up to rt, and then refluxed for 3 hr. The reaction mixture was then cooled to rt and ethanol (4.4 mL, 75 mmol) was added dropwise, followed by NaOH (11.51 ml, 46 mmol, 4.0 M in water). The resulting mixture was cooled to 0° C. and 35% hydrogen peroxide (10 mL, 115 mmol) was added. The resulting suspension was stirred at rt overnight. The reaction mixture was diluted with brine (125 mL) and ether (200 mL). The organic layer was washed with brine (2×125 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (330 g), eluting with 0-100% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.33 (d, J=6.6, 3H), 1.67 (m, 3H), 1.70 (m, 1H), 3.65 (m, 2H), 3.80 (m, 3H), 3.98 (m, 1H), 4.02 (m, 1H), 4.56 (d, J=11.8, 1H), 4.63 (t, J=12.2, 2H), 4.69 (d, J=12.0, 1H), 4.78 (dd, J=12.1, 2.1, 2H), 7.27-7.40 (m, 15H).
Reaction SMILES: C([NH:8][C:9]1[N:13]([CH2:14][CH2:15][O:16][CH3:17])[N:12]=[C:11](Br)[C:10]=1[N+:19]([O-])=O)C1C=CC=CC=1.[ClH:22]>C(O)C.[Pd]>[ClH:22].[ClH:22].[NH2:19][C:10]1[CH:11]=[N:12][N:13]([CH2:14][CH2:15][O:16][CH3:17])[C:9]=1[NH2:8]
Reactant: COCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCCn1ncc(N)c1N
Reaction time: 1 h

Procedure:
A mixture of 5-benzylamino-3-bromo-1-(2′-methoxyethyl)-4-nitropyrazole (4 g, 2.8 mmol) in ethanol (500 ml) containing a 10% Pd/C catalyst (Johnson-Mattey Type 487, dry weight 0.5 g) and 36% hydrochloric acid (0.57 g, 5.6 mmol) is hydrogenated in a Parr Autoclave (1 l) at 1 MPa for 1 hour. The catalyst is then removed by filtration and washed with ethanol, and the filtrate is evaporated under reduced pressure. A crude orange-coloured solid (2.8 g) is thus obtained, and is triturated in EtOAc (20 ml) for 1 hour. The solid is then filtered off and washed with cold EtOAc (20 ml) and then dried under vacuum to give the 4,5-diamino-1-(2′-methoxyethyl)pyrazole in the form of a beige-coloured solid (0.7 g, 27%).