Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34](=[O:37])[C:35]#[CH:36]>C(Cl)Cl.C1N2CCN(CC2)C1>[C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH:36]=[CH:35][C:34](=[O:37])[CH3:33])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: C#CC(C)=O
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OC=CC(C)=O)[C@H](C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A round bottomed flask was charged with tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (400 mg, 0.886 mmol) in CH2Cl2 (4429 μl). To the solution was added DABCO (4.97 mg, 0.044 mmol) and the reaction mixture was cooled to 0° C. under N2. Upon addition of but-3-yn-2-one (83 μl, 1.063 mmol), the colorless solution became dark brown-orange. After stirring for 2 h, the reaction mixture was concentrated and purified directly by column chromatography on SiO2 (0→10%, hold, 10→20%, hold, 20→50% hold EtOAc/hexanes gradient) to afford the title compound as a thick colorless oil (257 mg, 55.8%): 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=12.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.75 (d, J=12.4 Hz, 1H), 5.06-4.85 (m, 2H), 4.82-4.73 (m, 1H), 4.61-4.50 (m, 1H), 4.26-4.14 (m, 1H), 3.78 (s, 3H), 3.37-3.26 (m, 3H), 2.82 (dd, J=13.6, 4.0 Hz, 1H), 2.41-2.28 (m, 1H), 2.24-2.01 (m, 1H), 2.18 (s, 3H), 1.62-1.39 (m, 12H), 1.34 (d, J=6.4 Hz, 3H), 1.26 (t, J=7.1 Hz, 2H), 0.92 (dt, J=13.6, 4.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 197.24, 173.18, 163.24, 158.03, 155.34, 131.19, 129.61, 113.83, 108.08, 88.73, 88.61, 81.19, 76.86, 76.23, 75.39, 72.61, 72.49, 58.42, 56.97, 55.41, 55.14, 44.87, 35.82, 30.38, 29.45, 28.43, 28.27, 28.16, 26.38, 26.18, 19.16, 18.24; ESIMS m/z 542.4 ([M+Na)]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].Cl.CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (240 mg, 0.48 mmol) was dissolved in THF (3.2 mL) and treated with 4M HCl (1.6 mL, 0.8 mmol). The reaction mixture was heated to 45° C. and stirred at ambient temperature. After 2 h, methanol was added (15-20 drops) and the solution was stirred for 3 h. An additional portion of 4M HCl (1.6 mL, 0.8 mmol) and methanol (1 mL) were added and the solution was stirred 16 h at ambient temperature followed by 40° C. for 4 h. The solution was partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate (sat. aq.) and brine, dried over sodium sulfate and concentrated to 233 mg (quantitative yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[OH:23])=[CH:18][CH2:17]2)=[CH:11][CH:10]=1.[BH4-].[Na+]>C(O)C.O>[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][C:19]([CH:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[OH:23])=[CH:18][CH2:17]2)=[CH:11][CH:10]=1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)C=C1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 47.5 %

Procedure:
A stirred solution of 1.0 gram (0.0021 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-pyridyl)}[4-(trifluoromethyl)phenyl]methanol, hydrochloride salt in 30 mL of ethanol was cooled in an ice-water bath, and 0.1 gram (0.0026 mole) of sodium borohydride was added in one portion. Upon completion of addition, the reaction mixture was stirred at about 10° C. to 20° C. during a three-hour period. After this time the reaction mixture was diluted with 100 mL of water and extracted with two 75 mL portions of ethyl acetate. The combined extracts were washed with one 75 mL portion of aqueous 10% lithium chloride, and the combination was dried with sodium sulfate. The mixture was then filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on neutral alumina (6% water) using 1% to 2% methanol/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.44 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]([OH:24])([CH3:23])[CH:7]=[CH:8][CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:10]1[CH:9]([CH:8]=[CH:7][C:6]([OH:24])([CH3:23])[CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:13][CH2:12][C:11]1=[O:14])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCO
Solvent: c1ccncc1
Solvent: O
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCOC(C)=O
Reaction time: 72 h

Procedure:
A solution of 7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol [0.4 g; prepared as hereinbefore described in Example 7(iv)] in dry pyridine (4 ml.) was treated with acetic anhydride (4 ml.) and the resulting solution was allowed to stand at ambient temperature for 3 days and then diluted with water (100 ml.) with external cooling by means of an ice-bath. The resulting aqueous solution was extracted three times with chloroform, and the combined extracts were dried over sodium sulphate. Evaporation in vacuo gave a crude product which was purified by preparative thin layer chromatography on silica gel using a mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give 2-(7-acetoxyheptyl)-3-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)cyclopentanone (0.17 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(NC(C)=O)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl) -benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/2). Yield 90 mg. MS (ES+): m/e=548 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:8][CH3:9])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:3](=[O:10])[N:4]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[C:5]([S:8][CH3:9])=[N:6][N:7]=1
Reactant: CSc1nnc(C)c(=O)[nH]1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nnc(C)c(=O)n1Cc1ccccc1C#N
Temperature: 0 °C

Procedure:
To a solution of 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5, 1.546 g, 9.85 mmol) in dry DMF (10 mL) at 0° C. was added K2CO3 (1.36 g, 9.85 mmol) and 2-cyanobenzylbromide (2.316 g, 11.82 mmol). The mixture was heated at 0° C. for 16 h. The mixture was diluted with water, and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried over MgSO4, and concentrated. This was purified by column chromatography on silica gel, and eluted with 20% to 50% ethyl acetate in petroleum ether and 1:1:2 petroleum ether-dichloromethane-ethyl acetate to provide 2-((6-methyl-3-(methylthio)-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (6). MS: m/z, 273 (100%, M+1), 295 (60%, M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:11]([CH2:15][CH3:16])[C:12]([NH:23][CH2:21][CH3:22])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCC(C(=O)O)N(CC1CC1)c1ccc(C#N)c(Cl)c1
Reactant: CCN
Product: CCNC(=O)C(CC)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(3-chloro-4-cyanophenyl)(cyclopropylmethyl)amino]butanoic acid and ethylamine: MS (ES) m/z 320 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:22]([CH2:23][CH2:24][OH:25])[CH3:21])=[O:13])[CH2:8]2
Reactant: CNCCO
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CN(CCO)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 2-(methylamino)ethanol (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-[(2-hydroxy-ethyl)-methyl-amino]-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (29 mg, 29%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:15][Br:36])[CH:3]=1
Reactant: OCc1cc(Br)cc(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-4′-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) were combined in tetrahydrofuran (8 mL) and cooled to 0° C. N-Bromosuccinimide (0.59 g, 3.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.60 (m, 1H), 7.50-7.54 (m, 3H), 7.47 (m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:13][CH2:12][CH2:11][CH:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[CH2:26][CH2:25]1
Reactant: O=CCCC1CC(c2cccs2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccs3)=NO2)CC1
Yield: 92.4 %

Procedure:
3-(3-(2-Thienyl)-4,5-dihydroisoxazol-5-yl)propanal (21.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.0 mg (92.3%) of the target compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:29]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Temperature: 0 °C
Yield: 92.7 %

Procedure:
To a solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.392 g, 1.07 mmol) in dichloromethane (10 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.208 g, 2.14 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.522 g, 1.18 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.304 g, 2.35 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 112 g, 60% to 100% ethyl acetate/hexanes) which afforded (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.441 g, 92%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O4 [M+H]+ 445.2246, observed 445.2246, 1H NMR (300 MHz, DMSO-d6) δ 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.36-1.47 (m, 1H), 1.49 (s, 6H), 1.52-1.65 (m, 1H), 1.67-1.82 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.81 (s, 1H), 4.88 (dd, J=10.7, 5.0 Hz, 1H), 5.42 (s, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.29-7.40 (m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51-7.60 (m, 1H), 10.73 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[N:45][C:46]=1[CH3:47]>ClCCl.C(N(CC)CC)C>[OH:49][C:42]1[C:41]([CH2:40][NH:39][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:46]([CH3:47])[N:45]=[C:44]([CH3:48])[N:43]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1nc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A mixture of 4-phenoxybenzoic acid (92 mg, 0.43 mmol), 1-hydroxybenzotriazole (80 mg, 0.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.6 mmol), triethylamine (0.16 mL) and dichloromethane (15 mL) was stirred at 25° C. for half an hour. Then 5-(aminomethyl)-2,6-dimethylpyrimidin-4-ol (60 mg, 0.4 mmol) was added. The mixture was stirred at 25° C. for 12 hours and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((4-hydroxy-2,6-dimethylpyrimidin-5-yl)methyl)-4-phenoxybenzamide as a white solid (30 mg, 21%). LRMS (M+H+) m/z: calcd 349.14. found 349. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 12.36 (s, 1H), 8.35 (t, J=4.5 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.42 (t, J=8.4 Hz, 2H), 7.24-6.97 (m, 5H), 4.25 (d, J=4.5 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12]([C:14]1[O:15][C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=2[C:18]=1[N:19]=[CH:20]N(C)C)=[O:13])C.C(O)(=O)C>O1CCCC1>[OH:13][C:12]1[C:2]([C:1]#[N:3])=[CH:20][N:19]=[C:18]2[C:17]3[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=3[O:15][C:14]=12
Reactant: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cnc2c(oc3ccccc32)c1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A solution of 1.5 mL (30.0 mmol) of acetonitrile in 30 mL of tetrahydrofuran is added to a −78° C. solution of 11.4 mL of 2.5 M n-butyllithium (29.00 mmol) in 35 mL of tetrahydrofuran. After stirring at −78° C. for 15 min a solution of 3.7 g (14.2 mmol) of 3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic acid ethyl ester in 50 mL of tetrahydrofuran is added dropwise. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to 0° C. The reaction mixture is cooled to −78° C. and 3 mL of acetic acid is added. The solution is warmed to room temperature and the resulting precipitate is collected. This solid is combined with 20 mL of acetic acid and heated at reflux temperature for 1.5 hours. The mixture is cooled to room temperature and the solid is collected by filtration washing with saturated sodium bicarbonate, water, diethyl ether and ethyl acetate to provide 2.45 g of a red solid, mp>310° C.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].[CH:7]1([C:10]2[NH:11][C:12]([I:16])=[C:13](I)[N:14]=2)[CH2:9][CH2:8]1>O.C(O)C>[CH:7]1([C:10]2[NH:14][CH:13]=[C:12]([I:16])[N:11]=2)[CH2:9][CH2:8]1
Reactant: Ic1nc(C2CC2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Ic1c[nH]c(C2CC2)n1
Yield: 65.9 %

Procedure:
Na2SO3 (10.42 g, 82.65 mmol) was suspended in 40 ml water and 20 ml ethanol. 2-Cyclopropyl-4,5-diiodo-1H-imidazole (3500 mg, 9.72 mmol) was added and the mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated to 20 ml and then filtered. The solid was dried for 5 hours at 50° C. under reduced pressure (<10 mbar) to get a light brown solid (1.50 g, 66%), MS: m/e=235.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([S:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:2]1.[OH-].[K+]>C(O)C.O>[O:1]1[CH:5]=[CH:4][C:3]([S:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: CCOC(=O)CCSc1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCSc1ccoc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.5 %

Procedure:
A mixture of ethyl 3-(3-furylthio)propionate (0.52 g, 0.0026 mole) and potassium hydroxide (0.29 g, 0.0052 m) in ethanol (25 ml) and water (1.0 ml) was stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo below 40° C., water (20 ml) was added to the residue and the solution extracted with methylene chloride (20 ml). The aqueous layer was acidified with 3NHCl, extracted with methylene chloride (3×25 ml) and the combined extracts washed twice with water. After drying over sodium sulfate, the solvent was evaporated in vacuo to give 0.15 g (33%) of oily product.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(O[C:11](=[O:24])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])C.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([N:13]1[CH2:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:11](=[O:24])[CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CNC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1,200 ml) solution containing N-benzyloxycarbonylglycine ethyl ester (156.3 g, 600.0 mmol) and then, under ice-cooling, sodium hydride (60% oil; 26.40 g, 660.0 mmol) was added thereto. After 10 minutes of stirring at the same temperature, the ice bath was taken off, and the mixture was stirred at room temperature for 20 minutes and then at 50° C. for 3 hours. After completion of the reaction, and under ice-cooling, the reaction solution was adjusted to about pH 3 by adding 10% citric acid aqueous solution and mixed with ethyl acetate, and the mixture was shaken and then subjected to separation of layers. The organic layer was separated and washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to obtain 196.7 g (600.0 mmol, quantitative) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][C:30]1[S:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1>C(Cl)Cl>[CH3:29][C:30]1[S:31][C:32]([S:36]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (116 mg, 0.35 mmol) was suspended in DCM (6 ml), and triethylamine (102 μl, 1.39 mmol) was added obtaining a clear solution. 2,4-Dimethylthiazole-5-sulfonyl chloride (88.0 mg, 0.42 mmol) was added, and the reaction was stirred at RT for 3 hours. The reaction was diluted with DCM and washed with water and brine. The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=85/15) to obtain (R)-quinuclidin-3-yl 2-(2,4-dimethylthiazole-5-sulfonamido)-2-phenylacetate (67 mg; 44.2% yield).