Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:29])[S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.13 g (3.25 mmol)) in DMF (7.0 ml), 4-chloro-2-nitro-N-[(trans)-β-styrenesulfonyl]aniline (1.00 g (2,95 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.32 ml (3.38 mmol)) was added. The resulting mixture was stirred at 80° C. for 3 hours, and then poured into water, extracted with diethyl ether. The extract was washed with 1% sodium hydroxide solution, water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Small amount of diethyl ether was added to the residue and crystals separated was filtered and washed to give 0.99 g (95%) of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O>CC(C)=O.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Yield: 94.9 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol (5 g, 18 mmole) in 75 ml acetone, 1 ml 12N HCl, and 50 ml water, was stirred for 2 hr. After dilution with an additional 50 ml water the solid was collected to give the product (4.0 g, 95%, mp: 166°-168° C.).
Reaction SMILES: [CH2:1]([Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14]O)=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:7]=2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]C(Br)(Br)Br>C1COCC1>[Br:43][CH2:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[NH:5][C:4]=1[Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:1][CH3:2]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCBr
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A solution 2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol (0.730 g; 2.13 mmol) in THF (6 mL) was added to a solution of triphenyl phosphine (0.836 g; 3.19 mmol) and perbromomethane (1.06 g; 3.19 mmol) in THF (12 mL) pre-stirred for 1 hour. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.449 g (52%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])[CH:6]=[CH:5]2
Reactant: CC1CCNCC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: CC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 4-methyl-piperidine (commercially available) according to the procedure described for Example A. MS (m/e): 268.5 (MH−, 100%)
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[C:10]3([C:18]4[C:27](=[CH:26][C:21]5[O:22][CH2:23][CH2:24][O:25][C:20]=5[CH:19]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: MS (ES+) m/z 479.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 52 %

Procedure:
A 5.00 g quantity of 5-chloro-4-hydroxy-2-pyridone and 3.66 ml of acetyl chloride were stirred in 250 ml of pyridine at room temperature for 3 hours. The reaction mixture was then concentrated and the concentrate was washed with ethyl acetate and water to produce 3.39 g of the title compound in a yield of 52%.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.CC1(C)[O:23][CH:22]2[CH:18]([C@@H:19]([CH2:33]O)[O:20][C@H:21]2[N:24]2[C:30](=[O:31])[NH:29][C:27](=[O:28])[C:26]([F:32])=[CH:25]2)[O:17]1>N1C=CC=CC=1>[O:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:33][C@H:19]2[O:20][C@@H:21]([N:24]3[CH:25]=[C:26]([F:32])[C:27](=[O:28])[NH:29][C:30]3=[O:31])[C@H:22]([OH:23])[C@@H:18]2[OH:17])=[O:13])[CH2:6][CH2:7]1
Reactant: CC1(C)OC2C(O1)[C@@H](CO)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Reactant: O=C(O)CCCCN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(CCCCN1CCOCC1)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.96 g (13.2 m-mol) of 5-morpholinopentanoic acid hydrochloride in pyridine (30 ml) was added 4.2 g (13.9 m-mol) of TPS, and the mixture was stirred for 15 minutes at room temperature. To this solution was added 2.00 g (6.62 m-mol) of 2',3'-O-isopropylidene-5-fluorouridine, and the mixture was stirred for 18 hours at room temperature. The reaction liquid was concentrated under reduced pressure and the residue was distributed in chloroform (50 ml) and an 8% aqueous solution of potassium carbonate (50 ml). The aqueous phase was extracted with chloroform (50 ml ×5) and the extracts were combined with the chloroform phase previously obtained. The chloroform phase was dried with Na2SO4 and concentrated and the residue was subjected to a separation-purification treatment by way of silica gel column chromatography (column size: 5×8 cm, developing solvents: chloroform and chloroform containing 2% methanol) whereby 1.17 g of 5'-O-(5-morpholinopentanoyl)-2',3'-O-isopropylidene-5-fluorouridine was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([O:19]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:21]>CO>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:21])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Reaction time: 8 h

Procedure:
To a solution of the compound 66 (13.7 g) in methanol (91 mL) was added 28% ammonia (91 mL) at room temperature and the solution was stirred overnight. The reaction solution was concentrated. Brine and ethyl acetate were added thereto and the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=1:0→97:3→95:5→90:10) to give the title compound (10.1 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](=[CH2:26])[C:23](Cl)=[O:24]>O1CCCC1>[F:20][C:21]([F:28])([F:27])[C:22](=[CH2:26])[C:23]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:24]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C(=O)Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC1(C)C2CC3CC(C2)CC1C3)C(F)(F)F
Temperature: 0 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 83.1 g (0.50 mol) of 2-methyl-2-adamantanol, 101.2 g (1.0 mol) of triethylamine and 200 g of tetrahydrofuran. Then 118.9 g (0.75 mol) of α-trifluoromethylacryloyl chloride was dropwise added to the content in the flask over a period of about 1 hour, while the content was maintained at a reaction temperature of about 0° C. Then the content was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was washed with water and then with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 101.2 g (yield: 70.3%) of the object 2-methyl-2-adamantyl α-trifluoromethylacrylate was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([OH:5])=[O:4].[C:12]([O:16][C:17](N=[N+]=[N-])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O>[C:12]([O:16][C:17]([NH:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([OH:5])=[O:4])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: NC(C(=O)O)C1=CSCCO1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1=CSCCO1
Temperature: 35 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
DL-α-Amino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetic acid (25.4 g.) is suspended in dimethylformamide (435 cc.); tert.-butoxycarbonyl azide (41.5 g.) and triethylamine (51 cc.) are added. The reagents are left in contact for 48 hours whilst stirring at a temperature of 35° C. The solution is concentrated under reduced pressure (1 mm Hg), the residue is taken up in water (300 cc.), and the pH is adjusted to 8.5 by adding a saturated sodium bicarbonate solution. The aqueous phase is extracted twice with ethyl ether (a total of 500 cc.) which is discarded, and is then acidified to pH = 3 by adding 4 N hydrochloric acid A product precipitates, which is filtered off and then dissolved in methylene chloride (600 cc.). The solution obtained is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg). DL-α-Tert.-butoxycarbonylamino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetic acid (26.2 g.), melting at 160° C is thus obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][OH:35])[CH2:33][O:32][CH2:31]1>C(#N)C>[OH:35][CH2:34][C:30]1([CH2:29][O:1][C:2]2[C:3]([O:20][CH3:21])=[C:4]([C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[CH2:12][CH2:13][C:14]4=[O:19])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:33][O:32][CH2:31]1
Reactant: OCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (115 mg, 0.843 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (153 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 27.6%).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=CC=1)(O)=O.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:11]([N:12]([CH2:29][C:30]1[CH:31]=[CH:32][C:23]([CH2:14][CH2:13][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:24][CH:25]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[C@@H:23]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=2[CH2:24]1)[CH3:10]
Reactant: C1CCNCC1
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 39 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and piperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Yield: 93 %

Procedure:
A solution (0.07 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (2 N solution, 15 eq.). The mixture was heated to reflux for 90 min then concentrated and acidified to pH 1 with aqueous HCl (6 N) and extracted with AcOEt. The combined organic phase was washed with brine then dried and concentrated to give the title compound (93%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][C:15](OC)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N(CCO)Cc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.44 g, 1.15 mmol) in methanol cooled to 0° C. was added sodium borohydride (0.13 g, 3.45 mmol) and the resulting mixture was heated to 65° C. for 16 h. Additional sodium borohydride (0.26 g, 6.90 mmol) was added to the reaction mixture and stirred further at 65° C. for 18 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (50%) to ethyl acetate (100%). ESI-MS m/z:355 (M+1), UV retention time: 1.27 min.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1.S(Cl)([Cl:35])=O>ClCCl>[Cl:35][CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCO)nc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 23, 75 mg, 0.18 mmol) in dichloromethane (5 mL). Thionyl chloride (25 μL, 0.35 mmol) was added and the resulting solution was stirred for 3 h at room temperature. The solvents were carefully removed under reduced pressure to yield 50 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.O.O[Li].O.Cl>C1COCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O)ccc1C(=O)O
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 4-hydroxy-2-methoxybenzoate (11 g, 60 mmol) in THF:H2O (100 mL:10 mL) was added LiOH.H2O (3 g, 71 mmol). The solution was stirred over 24 h and then made slightly acidic (pH 5) with 10% HCl (approx 15 mL). The reaction solution was extracted with CH2Cl2 (3×50 mL). The organic phase was dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure to afford the 4-hydroxy-2-methoxybenzoic acid as a clean white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].II.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2=[O:25]>CCOCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(=O)Nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
5.57 g of 1-bromo-2-methoxybenzene are added dropwise to a suspension of 0.72 g of magnesium in 15 ml of ether containing a few crystals of iodine, the reflux being maintained once it has started. At the end of the addition, the mixture is refluxed for 2 hours. A suspension of 2.7 g of 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THF is then added and the mixture is refluxed for 30 minutes. After cooling to RT, the reaction mixture is poured into a water/ice/concentrated HCl mixture and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is slurried in hot iso ether and the precipitate formed is spin-filtered off and washed with ether. 3 g of the expected product are obtained.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=1)([CH3:17])[CH3:16])=[C:13]=[O:14].C(N(CC)CC)C>C1COCC1>[CH2:25]=[C:24]([C:20]1[CH:19]=[C:18]([C:15]([NH:12][C:13]([NH:11][C@@H:5]2[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]2)=[O:14])([CH3:17])[CH3:16])[CH:23]=[CH:22][CH:21]=1)[CH3:26]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)N[C@H]2CN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of (R)-quinuclidin-3-amine dihydrochloride (120 mg, 0.603 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (119 mg, 0.597 mmol) in THF (3 mL) was added triethylamine (168 uL, 1.21 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with brine. The mixture was extracted with CHCl3 and the organic layer was dried (Na2SO4) and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea (163 mg, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (t, J=1.6 Hz, 1H), 7.44 (dt, J=1.9, 7.0 Hz, 1H), 7.41-7.33 (m, 2H), 5.35 (br s, 1H), 5.11 (p, J=1.4 Hz, 1H), 4.84 (s, 1H), 4.21 (d, J=7.5 Hz, 1H), 3.70-3.61 (m, 1H), 3.13 (ddd, J=2.3, 9.3, 14.2 Hz, 1H), 2.71-2.54 (m, 3H), 2.30-2.22 (m, 1H), 2.15 (dd, J=0.8, 1.4, 3H), 2.05-1.96 (m, 1H), 1.65 (s, 3H), 1.64 (s, 3H), 1.65-1.60 (m, 1H) 1.54-1.45 (m, 2H), 1.22-1.12 (m, 1H), 0.95-0.80 (m, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 157.4, 148.5, 143.8, 141.3, 128.4, 124.4, 123.8, 122.2, 112.6, 55.2, 53.4, 46.2, 46.1, 44.5, 30.5, 30.4, 25.0, 22.2, 17.7, 8.9 ppm. Purity: 97.5% UPLCMS (210 nm); retention time 0.83 min; (M+1) 328.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:25])[NH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:25])[N:21]([CH3:36])[CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc[nH]c3=O)cc2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15.5 mg, 0.036 mmol) in dry DMF (1 mL) was cooled to 0° C. Sodium hydride (60% in mineral oil, 3 mg, 2 equiv) was added. After 20 min, iodomethane (4.54 μL, 2 equiv) was added. The mixture was stirred another 20 min before being warmed to rt slowly and stirred for 2 h. LC-MS found the reaction completed. The mixture was quenched with satd aq NH4Cl (1 mL) and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 83% yield). LC-MS Method 1 tR=1.63 min, m/z 447 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[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>[CH2:12]([NH:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: CCCNC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-propylamine (Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (48.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (80.0 mg, 75%) was isolated by chromatography (0-10% EtOAc-hexanes) as an orange oil.