Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:33][CH2:34]1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
66 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(2,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: Br[CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.FC(F)(F)C([O-])=[O:35].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[OH:35][CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C2C(CCC(Br)c3ccccc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reaction time: 1 h

Procedure:
17 g of 4-[3-(3-bromo-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 500 ml of dioxane and, after addition of 34 ml of ˜40 percent tetrabutylammonium trifluoroacetate solution, heated to reflux for 24 h. The mixture was concentrated to about half the volume, mixed with water and methyl tert-butyl ether and separated into the phases. The organic phase is concentrated, and the residue is stirred with 500 ml of ethanol and 200 ml of concentrated ammonia at room temp. for 1 h. It is then again concentrated in vacuo, and the crude product is purified on silica gel with dichloromethane/methanol =30:1 as mobile phase. The alcohol is obtained as an oil. MS (ESI): 413 (M+H+), 395 (M+H+-H2O) [C26H24N2O3 M=412].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1)(=[O:3])[CH3:2].CCOCC.N(CCO)CCO>C1COCC1>[C:1]([C:4]1[N:5]=[C:6]([C@H:10]([CH3:11])[OH:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: OCCNCCO
Product: CC(=O)c1cccc([C@H](C)O)n1
Temperature: -18 °C
Reaction time: 24 h

Procedure:
(-)-DIP-Cl (about 70% in hexane, about 22 mmol) was evaporated under reduced pressure to remove hexane. The resulting oil was dissolved in THF (15 ml) and added over 5 minutes into the solution of 2,6-diacetylpyridine (Example 23, 1.0 g, 6.13 mmol) in THF (20 ml) which had been cooled to -18° C. with ice-salt bath. The resulting orange solution was stirred at -18° C. to room temperature for 24 hours. Ether (60 ml) was added. The solution was cooled to 0° C. and then (HOCH2 CH2)2NH (5 ml, 52 mmol) was added. The resulting suspension was stirred at 0° C. to room temperature for 6 hours and filtered through Celite. The filtrate was evaporated to dryness. The residue was taken into ether/hexane, and filtered again. This operation was repeated a few times until there was little solid left when the residue was treated with ether/hexane. The final residue was subjected to chromatography on silica gel column, eluted consecutively with hexane/AcOEt (8:1) hexane/AcOEt (1:4). The crude product obtained was subjected to chromatography on a silica gel column again, and eluted consecutively with hexane/AcOEt (8:1), hexane/AcOEt/Et3N (800:600;14), hexane/AcOEt (1;3). From hexane/AcOEt/Et3N (800:600;14) eluant, (S)-(-)-6-acetyl-a-methyl-2-pyridinemethanol was obtained. From hexane/AcOEt (1:3) eluant monitored by chiral GC column (fused silica capillary column, SUPLECO β-DEX# 120, 30 m×0.25 mm, 150° C.), (S,S)-(-)-α,α'-dimethyl-2,6-pyridinedimethanol pyridinedimethanol was obtained. Yield: 0.41 g (40%). EE: 98%, containing 0.5% meso-isomer. 1H-NMR (CDCl3): dH=7.68 (t, 3J(HH)=7.7 Hz, 1 H, H-gpy), 7.20 (d, 3 j(HH)=7.7 Hz, 2 H, H-bpy), 4.88 (q, 3J(HH)=6.6 Hz, 2 H, CH), 3.94 (s, broad, 2 H, OH), 1.49 (d, J(HH)=6.6 Hz, 6 H, CH3). 13C-NMR (CDCl3): dC=162.06 (C2,6), 137.64 (C4), 118.26 (C3,5), 69.18 (CHOH), 24.07 (CH3).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].Br[CH2:13][CH2:14][CH3:15]>CS(C)=O>[CH2:13]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9])[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: COC(=O)c1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCn1cccc1C(=O)OC
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 9 g potassium hydroxide in 25 ml dimethylsulfoxide are added 5 g methyl pyrrole-2 carboxylate and 10 g 1-bromo-propane. After stirring for one hour, the reaction mixture is poured over 100 g crushed ice, after which the solution is extracted with ethyl ether. After drying, the solvent is evaporated under reduced pressure, to give 5 g crude methyl 1-propyl-pyrrole-2-carboxylate.
Reaction SMILES: CS(O[CH:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([O:9][CH:10]([CH2:15][O:16][S:17]([CH3:20])(=[O:19])=[O:18])[O:11]2)[CH2:7]1)(=O)=O.[OH-].[K+]>>[CH3:20][S:17]([O:16][CH2:15][CH:10]1[O:11][CH:12]2[CH2:14][CH:8]([CH2:7][CH:6]=[CH:13]2)[O:9]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)OCC1OC2CC(CC(OS(C)(=O)=O)C2)O1
Agent: [K+]
Agent: [OH-]
Product: CS(=O)(=O)OCC1OC2C=CCC(C2)O1
Reaction time: 0.03 h

Procedure:
7-Methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane (280 mg) is added to 5 ml of a boiling 2n potassium hydroxide solution in absolute alcohol and the mixture is boiled for 2 minutes under reflux while stirring vigorously. The reaction mixture which has congealed to a crystalline solid is cooled and, after treatment with 5 ml of 8% sodium bicarbonate solution, extracted three times with methylene chloride. The combined extracts are dried with sodium sulphate and the solvent is distilled off under reduced pressure to leave as residue the crystalline racemic 3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]non-6-ene (m.p. 53°-56°).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2CCCCC2)[C:20]2C=CC=C[C:21]=2[C:26]2C(OC)=CC=CC=2OC)CCCCC1.C1(B(O)O)CC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)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]>[CH:26]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2CC2)cc1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 725.4 %

Procedure:
To a solution of methyl 4-bromo-2-hydroxybenzoate (3.00 g) in toluene (30.0 mL) were added tris(dibenzylideneacetone)dipalladium(0) (0.60 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.53 g), cyclopropylboronic acid (2.79 g) and sodium carbonate (3.44 g), and the mixture was stirred overnight at 100° C. under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.80 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([NH:19][C:20]2[C:25]([O:26]C(=O)CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[C:24]([Br:45])[CH:23]=[C:22]([Cl:46])[CH:21]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[Br:45][C:24]1[CH:23]=[C:22]([Cl:46])[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[C:25]=1[OH:26]
Reactant: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2OC(=O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2O)cc(C(C)(C)C)c1O
Yield: 98.3 %

Procedure:
A solution of N,O-Di-(3,5-di-t-butyl-4-hydroxy-phenylacetyl)-6-amino-2-bromo-4-chloro-phenol (58.1 g, 89.8 mM) in methanol (400 ml) and potassium carbonate (24.78 g, 180 mM) was stirred at room temperature for 10 minutes. The methanol was removed in-vacuo, the residue treated with 2N HCl (180 ml, 360 mM), and extracted with ethyl acetate (300 ml). The organics were dried (Na2SO4), evaporated in-vacuo, and the residue suspended in petroleum ether. The precipitate was collected to give 37.44 g (88.9%) of the title compound which was suitable for the next step.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/c1cc(C(C)(C)C)n[nH]1
Yield: 98.7 %

Procedure:
A mixture of 3-tert-butyl-1H-pyrazol-5-amine (5 g, 36 mmol, Alfa-aesar) and N,N-dimethylformamide dimethylacetal (153 mL, 1078 mmol, Aldrich) was refluxed overnight. The reaction mixture was then cooled, concentrated under reduced pressure and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-5% methanol in dichloromethane) to provide 6.9 g (99%) of the title compound. MS (ESI+) m/z 195 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([N:25]2[CH:29]([CH3:30])[CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:20]=[C:19]([Cl:32])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:32][C:19]1[CH:20]=[C:21]([C:23]([N:25]2[CH:29]([CH3:30])[CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1
Reactant: CC1CCC(C)N1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCC(C)N1C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of {2-[3-chloro-5-(2,5-dimethyl-pyrrolidine-1-carbonyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.260 g) in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml), stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was taken up into ethyl acetate and filtered through silica (50 g) to give the title compound (0.102 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:19]CC3C=CC=CC=3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([OH:19])[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1O
Yield: 97.9 %

Procedure:
A solution of 4.7 g (12.0 mmol) of 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butyl ester and 2.0 g of 10% Pd/C in 40 mL of DMF and 100 mL of methanol is shaken on Parr shaker at 40 psi for 18 hours. The hydrogenation is repeated twice more to bring the reaction to completion. The catalyst is filtered through a pad of Celite, is washed with methanol and solvent is evaporated to yield a residue which is dissolved in methylene chloride. This is then filtered through a short pad of Magnesol and is washed with methylene chloride and ethyl acetate. The filtrate is evaporated to yield 3.4 g of 3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid tert-butyl ester as a yellow solid, mp 262-263° C.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][C:18]([Br:28])=[CH:17][N:16]=2)[S:12][CH:13]=1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[Br:28][C:18]1[CH:19]=[C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[N:10]=2)=[N:16][CH:17]=1
Reactant: CC(=O)NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)o1
Temperature: 50 °C
Yield: 30.1 %

Procedure:
To a mixture of N′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.100 g, 0.210 mmol) in 5 mL acetonitrile was added POCl3 (0.0769 mL, 0.840 mmol) and the reaction was heated at 50° C. for 72 hours. The mixture was concentrated to dryness, diluted with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and purified by preparative HPLC to give the title compound (0.029 g, 30.1% yield). 1H NMR (d6 DMSO) δ 2.50 (2, 3H), 3.00 (t, J=7.4 Hz, 2H), 3.17 (t, J=7.5 Hz, 2H), 6.76 (s, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.2 Hz, 1H), 10.99 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]3[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]3[CH2:13]2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Reactant: Nc1ccc(Cl)cc1
Product: O=C(O)c1nc2n(n1)-c1cccnc1N(c1ccc(Cl)cc1)C2

Procedure:
using 8.91 g (0.033 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 20.90 g (0.164 mol) of p-chloroaniline there is obtained 5-(4-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/ethyl acetate, melts at 234°-237° with decomposition;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C:22]1=[O:28].C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)Cl.CCOCC>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])[C:22]1=[O:28]
Reactant: O=C1CCC(c2ccccc2F)C(=O)C1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: CC(C)(O)C#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2F)C(=O)C1C(=O)c1ccccc1C(F)(F)F
Reaction time: 1 h
Yield: 34.2 %

Procedure:
2-Trifluoromethylbenzoyl chloride (7.1 g, 0.034 mole) and 4-(2-fluorophenyl)-1,3-cyclohexanedione (7.0 g, 0.034 mole) were dissolved in methylene chloride. Triethylamine (4.1 g, 0.041 mole) was added dropwise and the resulting solution stirred for one hour. The solution was washed with 2 normal hydrochloric acid (2N HCl), 5% potassium carbonate solution, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 40 ml of acetonitrile. Triethylamine (1 equivalent) and acetone cyanohydrin (0.4 ml) were added and the solution stirred for 1 hour at room temperature. After dilution with ether (150 ml), the solution was washed with 2N HCl. The ether layer was then stirred with 100 ml of 5% copper (II) acetate. The resulting copper salt was filtered, washed with hexane, and stirred with 6N hydrochloric acid to destroy the salt. The acidic aqueous solution was extracted with ether. The ether solution was then washed with water and dried over MgSO4. Concentration of the ether solution under vacuum afforded 4.4 g of the desired product as a brown oil (34.2% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:31])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:24][CH:25]=1)=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2Br)C(C)C)cc1
Yield: 63.3 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (164 mg, 0.66 mmol) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (200 mg, 0.79 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.29 mL, 1.65 mmol) and PyBroP (462 mg, 0.99 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexanes gradient to afford the product as a solid (202 mg, 63%).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.O>C1COCC1.CCCCCC>[CH3:10][O:9][C:4]1[C:3]([CH3:11])=[C:2]([B:17]([OH:22])[OH:18])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: COc1ncc(C)c(I)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncc(C)c(B(O)O)c1C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-iodo-2-methoxy-3,5-dimethylpyridine (2.0 g) in THF (40 mL) was cooled to −78° C. A 2.69 M solution of n-butyllithium in hexane (6.5 mL) was added dropwise to the solution over 10 minutes. The mixture was stirred at −78° C. for 20 minutes. Triisopropyl borate (5.26 mL) was added dropwise to the mixture over five minutes. The mixture was stirred with warming to 20° C. over 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The aqueous layer was neutralized with citric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was then concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated solid was collected by filtration. This solid is called first crop. The filtrate was concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated title compound (551 mg) was collected by filtration. The first crop were suspended in ethyl acetate. Trituration was performed by adding a small amount of MTBE. The precipitated title compound (553.3 mg) was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated title compound (121:1 mg) was collected by filtration. The combined title compound (1.23 g) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:39][O:38][C:17]4=[CH:18][C:19]5[CH2:20][C@@H:21]([C:35](O)=[O:36])[N:22]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:23][C:24]=5[CH:25]=[C:16]4[O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.C[O:43][C:44](=[O:62])[C@@H:45]([NH2:61])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=2[CH3:60])=[CH:49][CH:48]=1>>[CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C@H:14]3[CH2:39][O:38][C:17]4=[CH:18][C:19]5[CH2:20][C@@H:21]([C:35]([NH:61][C@@H:45]([CH2:46][C:47]6[CH:52]=[CH:51][C:50]([C:53]7[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=7[CH3:60])=[CH:49][CH:48]=6)[C:44]([OH:43])=[O:62])=[O:36])[N:22]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:23][C:24]=5[CH:25]=[C:16]4[O:15]3)=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with cyclopentylmethanol according to General Procedure K and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg). The title compound (17 mg) was prepared from (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 781.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])[CH3:2].CN(C=O)C.S(Cl)([Cl:20])=O>>[CH2:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:20])=[O:7])[CH3:2]
Reactant: CCc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cccc(C(=O)Cl)c1C

Procedure:
3-Ethyl-2-methyl-benzoic acid (0.517 g) was refluxed in 3 mL of thionyl chloride with a drop of DMF for several hours. Thionyl chloride was removed in vacuo to yield 0.89 g (4.48 mmol) of 3-ethyl-2-methyl-benzoyl chloride. The acid chloride was dissolved in 5 mL of CH2Cl2 and added slowly and simultaneously but separately with 5 mL of aqueous NaOH (0.30 g, 7.5 mmol) to a solution of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (0.96 g, 4.36 mmol) dissolved in 10 mL of CH2Cl2 prechilled to −5° C. During the addition, the temperature was kept below 5° C. The mixture was allowed to warm slowly to room temperature and was stirred overnight. The organic layer was removed and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried, and solvent was removed in vacuo to give 1.5 g crude product. This residue was extracted with 100 mL of hexanes under reflux, and the hot extract was decanted from an oily residue and allowed to cool to room temperature, whereupon 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-ethyl-2-methyl-benzoyl)-hydrazide crystallized (0.56 g, m.p. 167-169° C., 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.43 (s, 1H), 7.18 (m, 1H), 7.1 (s, 2H), 7.03 (s, 1H), 7.0 (m, 1H), 6.35 (d, 1H), 2.58 (q, 2H), 2.3 (s, 6H), 1.95 (s, 3H), 1.6 (s, 9H), 1.15 (t, 3H). Dissolution of the oily residue and crystallization yielded a second crop of less pure material, 0.21 g.