Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15]C(Cl)=O)=[CH:9][CH:8]=1.[O:21]1CCC[CH2:22]1>CN(C)C1C=CN=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]([CH3:15])([CH3:19])[CH3:20])[C:22]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[O:21])=[CH:11][CH:12]=1
Reactant: CC#CCO
Reactant: CC(C)(CC(=O)Cl)Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Product: CC#CCOC(=O)C(c1ccc(Cl)cc1)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 2.43 ml 0.0325 mol) but-2-yn-1-ol and 3.97 g (0.0325 mol of 4-dimethylaminopyridine in 35 ml tetrahydrofuran is added dropwise, at 0°-5° C., a solution of 7.95 g 0.0325 mol 2-(4-chlorophenyl-3,3-dimethylbutyryl chloride in 25 ml tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and after one and a half hours worked up as follows: after removal of the tetrahydrofuran in vacuo, it was treated with water and stirred with ether, the ether phase was dried over magnesium sulphate and concentrated in vacuo. A colourless oil was obtained.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][CH:41]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 24.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.01 g), N-(6-bromo-2-pyridyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.138 g), the title compound (0.720 g) was obtained as colorless powder crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)=O.CC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:6]
Reactant: O=[N+]([O-])c1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)CCCCl)cc1
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of m-chloroperoxybenzoic acid (80%, 16.6 g, 86.3 mmol) in methylene chloride (100 mL) was added dropwise to a solution of 1-[(3-chloropropyl)thio]-4-nitrobenzene (20.0 g, 86.3 mmol) in methylene chloride (200 mL) maintained at -78° C. (dry ice/acetone bath). After 2 h the reaction was allowed to warm to ambient temperature (~1 h) and 200 mL of 10% aqueous sodium hydroxide was added. The layers were allowed to separate and the aqueous layer was extracted (100 mL) with methylene chloride. The combined organic extracts were washed (water, 100 mL), dried (MgSO4) and concentrated in vacuo. A 1.0 g sample of the residue (21.2 g) was chromatographed (Chromatatron, SiO2, 4000μ, 99/1, methylene chloride:methanol) to give 0.89 g (88%) of white solid, mp 72.5°-74.5° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[CH2:11]([OH:14])[C:12]#[CH:13]>CCN(CC)CC.[Cu]I.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>[OH:14][CH2:11][C:12]#[C:13][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10]
Reactant: C#CCO
Reactant: N#CCCc1ccsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: N#CCCc1ccsc1C#CCO
Temperature: 50 °C
Reaction time: 9 h
Yield: 61.1 %

Procedure:
To a stirred solution of 3-(2-bromo-thiophen-3-yl)-propionitrile 81 (0.5 g, 2.31 mmol), CuI (0.04 g, 0.23 mmol), PdCl2(PPh3)2 (0.08 g, 0.12 mmol) in NEt3 (6 mL) at room temperature was added propargyl alcohol (0.28 mL, 4.62 mmole) and the reaction mixture was stirred at 50° C. for 9 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: 50% EtOAc in hexane). The major fractions were combined and concentrated to give 82 (0.27 g) as a yellow syrup. 1H NMR (400 MHz, d6-DMSO) δ: 7.54 (d, J=5.0 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 5.37 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H), 2.84 (t, J=7.0 Hz, 2H). MS (EI) m/z (M−OH+) 174.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18]O)([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.N1C(C)=CC(C)=CC=1C.[F:42]C(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18][F:42])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CF)C3)n1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (227) (62 mg, 0.140 mmol) and 2,4,6-collidine (0.0359 mL, 0.271 mmol) in dry CH2Cl2 was added trifluoromethanesulfonic acid anhydride (0.0365 mL, 0.217 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 1 hr. TLC indicated that the reaction was complete. The reaction was quenched with 0.5 N aqueous HCl, extracted with 3×CHCl3, dried over Na2SO4, and concentrated. The residue was dissolved in anhydrous CH2Cl2 (3 mL), and TBAF (1 mL, 1 M in THF) was added. The resulting mixture was stirred at room temperature for 1.5 hr, quenched with H2O, and extracted with 3×CHCl3. The combined organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 50-65% EtOAc in hexanes to give a white solid (18 mg, 28% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H) 7.84-7.96 (m, 2 H) 7.25-7.31 (m, 2 H) 7.02-7.15 (m, 3 H) 6.72-6.83 (m, 1 H) 4.26-4.54 (m, 2 H) 3.79 (s, 3 H) 3.20 (d, J=16.67 Hz, 1 H) 3.08 (s, 3 H) 2.89 (dd, J=16.67, 1.77 Hz, 1 H) 1.52 (s, 3 H); LCMS for C22H22FN3O5S m/z 460.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](C=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.Cl.[N:32]1([CH2:38][CH2:39][O:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:41][O:40][CH2:39][CH2:38][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NOCCN1CCCCC1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4c3CC(=NOCCN3CCCCC3)C=C4)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
In a mixture of tetrahydrofuran (2 ml) and water (0.1 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 50 mg) and 2-(1-piperidyl)ethoxyamine dihydrochloride (36.5 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous saturated sodium bicarbonate solution, and aqueous sodium chloride solution, and dried over magnesium sulfate. After concentration, the residue was purified by chromatography (eluting with hexane:ethyl acetate=2:3) using an amino column, and further re-purified by thin layer chromatography to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(1-piperidyl)ethoxyimino)quinazoline (V-1, 13 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:5]
Reactant: COc1cc(C=O)ccc1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of OBS02011 (5.5 g, 21.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.88 g, 23.33 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02014 as a pale yellow oil (5.12 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.18; 1H-NMR (270 MHz, CDCl3), 2.44 (1H, bs, OH), 2.92 (6H, s), 3.84 (3H, s), 4.60 (2H, s), 6.85 (1H, dd, J=2.2, 8.4), 6.97 (1H, d, J=1.8), 7.25 (1H, d, J=8.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:14]([OH:16])=[O:15].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 250 ml of tetrahydrofuran were added at 10° C. to a mixture of 2.6 g of sodium hydride in 100 ml of tetrahydrofuran and the mixture was stirred at 15° C. for 30 minutes. A solution of 35 ml of benzyl bromide in 100 ml of tetrahydrofuran was added to the mixture which was heated at 50° C. for 48 hours and then was cooled and poured into aqueous monosodium phosphate solution. The mixture was extracted with isopropyl ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-isopropyl ether mixture to obtain 30 g of benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]=O)=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[CH2:21][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(NCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carbaldehyde (intermediate B4:1, 0.02 g, 0.06 mmol) in DCE was added methyl 4-aminobenzoate (0.01 g, 0.06 mmol), acetic acid (3.4 ul, 0.06 mmol) and NaBH(OAc)3 (0.015 g, 0.07 mmol). After Stirring at rt overnight, a drop of water was added to the reaction and purified by reverse phase HPLC to give methyl 4-[({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methyl)amino]benzoate. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=2.5 Hz, 1H), 8.05 (m, 2H), 737 (d, J=8.8 Hz, 2H), 7.44 (dd, J=8.4, 2.5 Hz, 1H), 7.14 (m, 2H), 6.90 (d, J=8.4 Hz, 1H), 6.61 (d, 3=8.8 Hz, 2H), 4.43 (s, 2H), 3.84 (s, 3H); HRMS exact mass calc for C23H17ClFN3O3S [M+H]: 470.0736; observed: 470.0734.
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>II.C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of I2 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2, 1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:42])C.[OH-].[Na+].Cl>C(O)C>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][O:32][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:43])=[O:3])=[C:8]([CH3:42])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:17]=2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCCc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 160 mg (89%). HPLC-MS: m/z: 607.1 (M+H)+; Rt: 2.82 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14].[CH2:15]=O>C(O)=O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:10][CH2:11][N:12]([CH:13]=[O:14])[CH2:15]2
Reactant: C=O
Reactant: COc1cccc(CCNC=O)c1C
Solvent: O=CO
Product: COc1ccc2c(c1C)CCN(C=O)C2
Temperature: 100 °C

Procedure:
To a solution of {2-[2-methyl-3-(methyloxy)phenyl]ethyl}formamide (Preparation 11; 1.93 g; 10.0 mmol) in formic acid (20 ml) was added paraformaldehyde (0.315 g; 10.5 mmol) and the resulting mixture was heated under reflux (100° C.) for 20 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a solution of 1-benzylpiperidin-4-amine (10 g) in dichloromethane (80 ml), cooled to 5° C., was added pyridine (5.1 ml) followed by acetyl chloride (4.5 ml) and the resulting mixture was stirred for 5 hours. The reaction mixture was washed with 1N NaOH (×2) and then the organic layers were dried and evaporated to dryness to give a solid which was recrystallised from ethyl acetate to give N-(1-benzylpiperidin-4-yl)acetamide. Yield 8.8 g. NMR (d6 DMSO): 1.4 (m, 2H), 1.7 (m, 2H), 1.8 (s, 3H), 2.0 (m, 2H), 2.75 (m, 2H), 3.45 (s, 2H), 3.55 (m, 1H), 7.3 (m, 5H), 7.75 (d, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CS(O[CH2:57][C:58]1([CH2:61][C:62]#[N:63])[CH2:60][CH2:59]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[C:62]([CH2:61][C:58]1([CH2:57][O:51][C:42]2[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=2)[CH2:39][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:60][CH2:59]1)#[N:63]
Reactant: CS(=O)(=O)OCC1(CC#N)CC1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC#N)CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate (appendage 4) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6]2.C(OCC)(=O)C.ClCCl>O1CCCC1.[O-2].[O-2].[Mn+4]>[O:12]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:6][O:7]1
Reactant: O=C1OCc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
5-(Hydroxymethyl)-1 (3H)-isobenzofuranone (2.94 g, 17.9 mmol) obtained from Example 4-(2) was dissolved in tetrahydrofuran (100 ml), and activated manganese dioxide (31 g) was added thereto. The mixture was stirred at room temperature for 30 minutes, and an additional amount of activated manganese dioxide (3 g) was added thereto. The resulting mixture was stirred for a further 30 minutes and then filtered. The solid filtered off was washed with tetrahydrofuran, and the washings were combined with the previous filtrate, then the combined solution was concentrated under reduced pressure to give a solid residue. The residue was subjected to chromatography on a silica gel (150 g) column (eluent; ethyl acetate:dichloromethane=0:1˜1:10). The eluate was concentrated under reduced pressure to afford a solid compound, which was washed with a mixed solvent of ethyl acetate-hexane (1:2) to afford the title compound (2.01 g, 69% yield) as a solid (mp. 160° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.[OH-].[K+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]([CH3:25])[C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: CI
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C#N)c3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of acetonitrile 18 (0.200 g, 0.682 mmole) in 10 mL dimethylformamide was added pulverized potassium hydroxide (0.046 g, 0.818 mmole) and methyl iodide (0.161 g, 0.818 mmole). After stirring at rt for 2 hours, the orange reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.087 g (42%) of propionitrile 19 as a white solid. Used as is for conversion to 21, infra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:13]([O-:15])=[O:14])=O.Cl.[C:25]1(C)C=CC=C[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5]/[CH:10]=[C:12](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)\[C:13]([O:15][CH2:25][CH3:26])=[O:14]
Reactant: COc1ccccc1N
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccccc1OC)c1ccc(OC)cc1
Yield: 54 %

Procedure:
A solution of 2-methoxyaniline (1.25 ml, 11.08 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (2.70 g, 1.1 eq) in toluene (20 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 1.96 g (54%) of compound 20 (Z isomer) in the form of a yellow oil which crystallizes from methanol.