Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:17])[CH:5]([CH:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]1)[C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:9]([S:8][C:6](=[O:7])[CH:5]([CH:11]1[CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:16]2)[CH2:12]1)[C:4]([S:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: OCCO
Reactant: CCSC(=O)C(C(=O)SCC)C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCSC(=O)C(C(=O)SCC)C1CCC2(C1)OCCO2
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 2-(3-oxo-cyclopentyl)-dithiomalonic acid di-S-ethyl ester (43.6 g, 0.159 mol), ethane-1,2-diol (49.3 g, 0.796 mol), p-toluenesulfonic acid (5.5 g, 0.032 mol) and benzene (500 mL) were heated to reflux and water was removed with a Dean-Stark trap. After 16 h, the mixture was quenched with water and saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried and concentrated to afford crude product. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% ethyl acetate/hexanes) afforded 2-(1,4-dioxa-spiro[4.4]non-7-yl)-dithiomalonic acid di-S-ethyl ester as a white solid (47.0 g, 92%).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH3:13])[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][C:15]1([CH3:36])[CH:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([OH:35])=[CH:20][CH:21]=2)[O:16]1.CC1(C)CC(C2C=CC(C(F)(F)F)=CC=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[CH2:2]([N:9]([CH2:10][CH2:11][O:35][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:24][C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:21][CH:20]=1)[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CN(CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1)Cc1ccccc1
Yield: 49 %

Procedure:
Reaction of N-benzyl-N-(2-chloroethyl)methylamine hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound (49%) as a colourless oil, The hydrochloride salt had m.p. 112°-115° C decomposed.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23]S(C)(=O)=O.[CH2:28](O)[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: OCCOCCOCCO
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO

Procedure:
Monodispersed compound 32 was prepared from compound 31 and monodispersed triethylene glycol using the procedure described above in Example 17. Oil; Rf 0.41 (methanol:chloroform=6:10); MS m/z calc'd for C21H44O11 472.29 (M++1), found 472.29.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:20][CH3:21])=[O:19].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1>[OH:26][CH:22]([C:14]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17][O:13]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C=O
Reactant: COC(=O)C1CCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)C(C)C)CCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
This procedure was adapted from J. Chem. Soc. Perkin Trans. I. 1997, p 771. To a solution of N,N-diisopropylamine (1 mL, 7.69 mmol) in THBF (13 mL) at 0° C. as added n-butyllithium (4.2 mL, 8.46 mmol, 2 M in hexanes). After stirring the mixture for 30 min, it was cooled to −78° C. and 2-tetrahydrofuroic acid, methyl ester (1 g, 7.69 mmol) in THF (13 mL) was added. The reaction mixture was stirred at the same temperature for 15 min and then warmed to −40° C. Isobutyraldehyde (1 mL, 11.5 mmol) was added and stirring was continued for 1 hr and −40° C. The reaction mixture was then warmed to 0° C. and stirred for 1 hr before it was quenched HCl (30 mL, 1M). Extracted with 2×50 mL of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate. Filtration and evaporation gave the crude product 2.63 g as an oil. Flash column chromatography on silica gel eluted with 15:85 ethyl acetate/hexane gave the desired product (688 mg, 44% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1>>[CH:17]1([CH:14]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:16])[O:12][C:11]=2[CH3:13])[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1cc(F)ccc1-c1cc(C=O)c(C)o1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1cc(C(O)C2CCCCC2)c(C)o1
Yield: 72 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-fluoro-2-methylphenyl)-2-methyl-3-furaldehyde (2.6 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (18 mL) to give the title compound (2.6 g, 72%) as an oil.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:53]=[CH:52][C:16]([C:17]([O:19][C:20]([CH3:51])([CH3:50])[C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:48][CH2:49]2)[CH:36]=1)[O:23][C:21](=[O:22])[C:20]([O:19][C:17](=[O:18])[C:16]1[CH:52]=[CH:53][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)[CH:15]=1)([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(OC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.6 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (168 mg, 0.192 mmol) in dry DCM (2 ml), HCl 4M in dioxane (144 μl, 0.577 mmol) was added with stirring at RT for 2 days. Additional HCl 4M in dioxane (144 μl, 0.577 mmol) was freshly added and the stirring was continued for further 3 days. The volatiles were removed under vacuum, and the crude was purified by preparative HPLC. After evaporation of the solvent, the residue was triturated with iPr2O and collected by filtration to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)-2-methylpropanoyloxy)ethyl)pyridine 1-oxide as a white solid (50 mg, 0.065 mmol, 33.6% yield, MS/ESI+ 773.29 [MH]+, [αD]=−18.13, c=0.60, MeOH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1COCC1>[CH2:27]([N:14]([CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:15][CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1NC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred slurry of 11 g of lithium aluminum hydride in 250 ml anhydrous THF under nitrogen was added dropwise a solution of 43.6 g of 2-[bis(phenylmethyl)amino]-N-(2-methoxyphenyl)acetamide in 500 ml anhydrous tetrahydrofuran and stirred overnight at room temperature. After cooling to 0°, the mixture was treated cautiously in succession with 50 ml of water. The granular precipitate was separated by filtration and washed several times with methylene chloride. The filtrate was evaporated to dryness, the residue dissolved in either and the organic phase extracted with 3 N hydrochloric acid. the water phase was made alkaline with 3 N sodium hydroxide and the base extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and evaporated at reduced pressure. The crude syrup (36.9 g) was chromatographed on silica gel column packed in methylene chloride. Elution with methylene chloride provided N,N-dibenzyl-N'-(2-methoxyphenyl)ethylenediamine (22.8 g) in the form of an oil.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH:1]1([N:5]([CH3:31])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)NC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)N(C)C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-benzamide (1.67 grams, 4.51 mmol) in N,N-dimethylformamide (50 mL) at 0° C. under nitrogen was added NaH (60% dispersion in mineral oil, 0.27 grams, 11 mmol). After stirring 30 minutes at 0° C., iodomethane (3.2 g, 23 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours, poured into water (450 mL), and extracted with ethyl acetate (3 times 75 mL). The combined organic extracts were washed with water (5 times 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexane to 40% ethyl acetate in hexane) to afford the title compound (1.65 grams) as an off white foam. 1H NMR (400 MHz, CDCl3) δ7.96 (s, 2H), 6.80-6.52 (m, 3H, 2 rotomers observed), 5.04, 4.02-3.98 (m, m, 1H, 2 rotomers observed), 3.74, 3.67 (s,s, 3H, 2 rotomers observed), 3.02, 2.75 (s,s, 3H, 2 rotomers observed), 2.25-1.94 (m, 9H, 2 rotomers observed), 1.75-1.41 (m, 3H, 2 rotomers observed). MS (APCI+) Calc: 384.0, Found: 385.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCOCCCCCCBr
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynyl ether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5 g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) in tetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogen for 20 mins. Copper (I) iodide (12.5 g) was then added to give a dark red/brown mixture that was heated to 50° C. for 23 h. The reaction mixture was then cooled to room temperature and filtered through a short silica pad (1000 g). The pad was washed with additional tetrahydrofuran (15.6 L) and the resulting solution then concentrated under reduced pressure to give crude product (1382 g) as a viscous oil. This was purified by chromatography (7 kg silica) eluting with 5:1 petroleum ether:ethyl acetate followed by 2:1 petroleum ether:ethyl acetate to give the title compound (932.9 g) as an oil, LC RT=5.69 min, δ (DMSO-d6) 7.79 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55 (2H, t, J 6.6 Hz), 3.49 (2H, t, J 6.6 Hz), 3.42 (2H, t, J 6.6 Hz), 2.68 (2H, t, J 6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).
Reaction SMILES: [H-].[Na+].C1COCC1.[N:8]1([CH2:14][CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27](F)=[CH:26][C:24]=2[N:25]=1)[CH3:19]>O>[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27]([O:17][CH2:16][CH2:15][CH2:14][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:26][C:24]=2[N:25]=1)[CH3:19]
Reactant: OCCCN1CCOCC1
Reactant: CCc1nc2cc(F)ccc2[n+]([O-])n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cc(OCCCN3CCOCC3)ccc2[n+]([O-])n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
NaH (60% dispersion in oil, 310 mg, 7.75 mmol) was added to dry THF (10 mL) and stirred at 20° C. for 20 min prior to the addition of 3-(4-morpholinyl)propanol (676 mg, 4.66 mmol). The mixture was stirred for 30 min, fluoride 28 (300 mg, 1.55 mmol) added and the resulting solution stirred at 20° C. for 2.5 h under N2. Water was added and the solution extracted with DCM (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-5%) MeOH/DCM to give 1-oxide 31 (257 mg, 52%) as a pale yellow solid, mp 108-111° C.; 1H NMR δ 8.33 (d, J=9.3 Hz, 1 H, H-8), 7.21-7.26 (m, 2 H, H-7 and H-5), 4.22 (t, J=6.4 Hz, 2 H, CH2), 3.73 (t, J=4.6 Hz, 4 H, 2×CH2O), 3.00 (q, J=7.6 Hz, 2 H, CH2), 2.55 (t, J=7.0 Hz, 2 H, CH2), 2.48 (t, J=4.6 Hz, 4 H, 2×CH2N), 2.06 (m, 2 H, CH2), 1.43 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 168.7, 164.6, 150.3, 128.4, 123.1, 121.6, 106.3, 67.3 (2), 66.9, 55.1, 53.7 (2), 30.7, 26.0, 12.2. Anal. Calcd for C16H22N4O3: C, 60.4; H, 7.0; N, 17.6. Found: C, 60.4; H, 7.0; N, 17.4%.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
To a solution of 3-buten-1-ol (540 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 650 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:35]1([CH2:40][CH2:41][O:25][C:22]2[CH:21]=[CH:20][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:24][CH:23]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OCCC1CCCC1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCCC2CCCC2)cc1)O3
Temperature: 25 °C

Procedure:
(S)-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 dissolved in DCM and cyclopentane-ethanol (5 eq.), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 9:1 hexanes EtOAc to 7:3 hexanes EtOAc). This ester was hydrolyzed according to General Procedure AB to give (3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride according to General Procedure L to give (S)-2-{[(3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z): 811.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=2[C:24]2C=CC=[CH:26][CH:25]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cccc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 mL) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reaction mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Most of the solvent was removed and saturated NaHCO3 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H) 8.63 (br. s., 1H) 8.34 (s, 1H) 7.85 (d, J=8.34 Hz, 1H) 7.39-7.51 (m, 7H) 5.99 (s, 1H) 5.03 (quin, J=6.57 Hz, 1H) 4.22 (d, J=4.29 Hz, 2H) 2.21 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS (ES) [M+H]+ 367.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Solvent: ClCCl
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A three-necked round bottom flask was charged with the product from Example 6 (59.0 g, 0.182 mol) followed by CH2Cl2 (1.18 L). The resulting suspension was stirred briefly before adding allyltrimethylsilane (58 ml, 0.364 mol) all at once at room temperature. The suspension was cooled to 0° C. under nitrogen and was treated with BF3OEt2 (46.3 ml, 0.364 mol) dropwise keeping the reaction temperature below 2° C. After complete addition, the mixture was stirred at 0° C. for ˜1 hour. The completion of the reaction was monitored with HPLC until the starting material was consumed. The reaction mixture was poured into saturated NaHCO3 solution and stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, treated with charcoal, filtered and concentrated to an oil. EtOH (200 ml) was added and the solution was concentrated to give a crystalline solid which was suspended with heptane at 0° C. for 2 hours before filtration to give a solid which was dried under reduced pressure at 45° C. to provide the title compound as a light yellow crystalline solid (60.1 g, 95.1%). Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; Found: C, 79.26; H, 7.12; N, 3.80, 1H NMR [(CD3)2SO] δ1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, m), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, t,), 7.96 (1H, d); 13C NMR [(CD3)2SO] δ23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2, 133.8, 134.5, 145.8, 151.1, 156.4. MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:10]([NH:17][C:7](=[O:9])[C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CC[C@H](C(=O)NCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Oxo-D-proline (5.0 g), benzylamine (4.65 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g) and 1-hydroxybenzotriazole (6.3 g) were mixed in acetonitrile (100 mL) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 3 hr. The mixture was diluted with ethyl acetate (200 mL), and washed successively with 1M hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (4.02 g) as a white powder.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1.[CH3:11][OH:12]>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([O:12][CH3:11])=[N:5][CH:6]=1
Reactant: CO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Br)cn1

Procedure:
Sodium hydride (2.0 g of a 60% dispersion in mineral oil) was added portionwise to methanol (30 ml) with stirring and cooling with an ice-bath. 2,5-Dibromopyridine (2.37 g) was added to the mixture and the mixture stirred at reflux for 16 hours. The methanol was removed by evaporation. Water (15 ml) was added to the residue and the mixture was extracted with dichloromethane (3×15 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give 5-bromo-2-methoxypyridine (2.0 g) as an oil, NMR: 3.85(3H,s), 6.83(1H,d), 7.9(1H,dd) and 8.3(1H,d).