Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([CH:22]3[N:26]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[CH:25]([C:37]4[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[O:45])=[CH:39][CH:38]=4)[CH2:24][CH2:23]3)=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([N:26]2[C@@H:22]([C:20]3[CH:19]=[CH:18][C:16]4[NH:17][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:14][C:15]=4[CH:21]=3)[CH2:23][CH2:24][C@@H:25]2[C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]([C@@H:46]3[CH2:50][CH2:49][CH2:48][NH:47]3)=[O:45])=[CH:41][CH:42]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(C2CCC(c3ccc4[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)nc4c3)N2c2ccc(C(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2[C@@H](c3ccc(NC(=O)[C@@H]4CCCN4)cc3)CC[C@@H]2c2ccc3[nH]c([C@@H]4CCCN4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a solution of the product from Example 179H (0.302 g, 0.389 mmol) in CH2Cl2 (3 mL) was added TFA (2.5 mL), and the resulting mixture was stirred at rt for 1.5 h. The mixture was concentrated in vacuo, and the crude product was purified by reversed-phase HPLC (C18) using a solvent gradient of 10-100% acetonitrile in H2O (0.1% TFA). The trans-pyrrolidine isomer eluted before the cis-pyrrolidine isomer. Fractions containing the trans-isomer were concentrated in vacuo, and the residue was partitioned between CH2Cl2 and saturated aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (83 mg, 37%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]1([CH:20]([CH3:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)=[O:25]>>[C:14]1([CH:20]([CH3:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:1]([O:7][OH:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[CH3:2].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: c1ccccc1
Solvent: Oc1ccccc1
Solvent: CC(C)c1ccccc1
Product: CC(C)(OO)c1ccccc1

Procedure:
The industrial synthesis of phenol comprises the alkylation steps of benzene to cumene, the oxidation of cumene to cumyl hydroperoxide and the subsequent rearrangement to give phenol and acetone.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][N:11]=[CH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CC1CCCO1>[Si:1]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:29][CH2:30]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Solvent: CC1CCCO1
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Reaction time: 6 h

Procedure:
To a hydrogenation flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylimino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (4.6 g) and 2-methyltetrahydrofuran (50 mL). The resulting mixture was stirred until the solid dissolved (about 5 min.) and then the mixture was purged with nitrogen. Platinum on carbon (920 mg, 5 wt. %, support activated carbon) was added and the mixture was hydrogenated at 50 psi (Parr shaker) for 6 hours. The mixture was then filtered through Celite and the Celite was washed with 2-methyltetrahyrofuran (10 mL). To the filtrate was added a thiopropyl-modified silica gel (20% of weight of solution, Silicycle) and this mixture was stirred at 25° C. to 30° C. for 3 hours. The mixture was then filtered through Celite and concentrated to remove the solvent. The residue was dissolved in methanol (5 mL per gram of residue) and then the resulting solution was added slowly to a vigorously stirred 1:1 mixture of saturated aqueous sodium bicarbonate and water (40 mL per gram of residue). The resulting off-white slurry was stirred for 20 minutes and then filtered. The filter cake was washed with water (20 volumes), air dried for 3 hours and then dried in vacuum at room temperature overnight to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (80% recovery, about 96% purity).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: O=Cc1cccc(O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Oc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 3-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: C(OC(C[C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=O)C=C.[Cl:20][C:21]1[CH:22]=[C:23]([NH2:30])[C:24](=[CH:28][CH:29]=1)[C:25]([OH:27])=O.[OH2:31]>C1COCC1>[CH2:22]([O:31][C:8]1[C:9]([CH:24]=[C:25]=[O:27])=[C:10]([S:14]([N:17]2[C:25](=[O:27])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=3)[NH:30][C:18]2=[O:19])(=[O:15])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH:21]=[CH2:29]
Reactant: C=CCOC(=O)Cc1cccc(S(=O)(=O)N=C=O)c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O
Solvent: C1CCOC1
Product: C=CCOc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1C=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Following the Synthesis Method (A), 3.27 g (11.6 mmol) of 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100 ml of anhydrous THF, then 1.98 g (11.5 mmol) of 4-chloroanthranilic acid was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol) of CDl was added and the resultant mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the mixture was extracted with ethyl acetate. The organic layer was washed, dried, and concentrated to obtain a crude product. This was crystallized with a small amount of ethyl acetate to obtain 2.0 g (yield 40%) of 3-(3-allyloxy-carbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. The allyl product thus obtained was dissolved in 100 ml of a formic acid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. The reactor was shaded from light and under nitrogen atmosphere, then 700 mg of tetrakis(triphenylphosphine)palladium (0) was added and the resultant mixture was stirred while shaded at room temperature overnight. The reaction solution was concentrated in vacuo and the solid obtained was washed with methylene chloride to obtain 1.47 g (yield 81%) of the above-identified compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1-c1ccc(Cl)cc1
Yield: 51.1 %

Procedure:
The title compound was prepared from 4′-chloro-1,1′-biphenyl-2-amine (3.5 g, 17.19 mmol), acetic anhydride (1.79 mL, 18.9 mmol), pyridine (3.2 mL, 39.5 mmol), and 4-(N,N-dimethylamino)pyridine (0.06 g, 0.52 mmol) according to the procedure and in the same manner as described in Example 60, step b. The crude product was purified by re-crystallization from a mixture of ethyl acetate-hexane to yield N-(4′-chloro-1,1′-biphenyl-2-yl)acetamide (2.16 g, 8.78 mmol, 51%) as a white solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>>[NH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:36][CH2:35][CH:32]3[CH2:34][CH2:33]3)=[O:24])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:38][CH2:39]1
Reactant: NCC1CC1
Reactant: NC1CCNCC1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using (cyclopropylmethyl)amine for the amide formation and 4-piperidinamine for the displacement reaction: LC-MS m/z 545 (M+H)+, 1.63 min (ret time).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37]>>[NH2:38][C:36](=[O:37])[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(N)=O
Product: CON=C1C[C@@H](C(=O)NCC(N)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-aminoacetamide, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=395.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]([C:12](=[O:15])[CH2:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O)C>[I-].C[N+]1C(C)=C(CCO)SC=1.ClCCl>[O:15]=[C:12]([CH:7]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1)[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:13][CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)C(=Cc1ccc(F)cc1)C(=O)OC
Agent: Cc1c(CCO)sc[n+]1C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCC(=O)C(C(=O)OC)C(C(=O)c1ccccc1)c1ccc(F)cc1
Yield: 28.5 %

Procedure:
A mixture of methyl 2-(4-fluorobenzylidene)-3-oxopentanoate (52.0 g), benzaldehyde (25.4 g), triethylamine (22 g), 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide (6.3 g) and ethanol (100 ml) was heated at reflux under nitrogen for 16 hours. The cooled mixture was diluted with dichloromethane, and washed with dilute hydrochloric acid (2N), with dilute aqueous sodium bicarbonate solution, and with water, and dried over magnesium sulphate. The solution was concentrated in vacuo and the residue was dissolved in hot methanol. The resulting off-white solid was filtered off, to give methyl 2-(1-oxopropyl)-3-(4-fluorophenyl)-4-phenyl-4-oxobutanoate (21.5 g), m.p. 104°-109° C. [Elemental analysis: C,70.1;H,5.42;F,5.58%; calculated: C,70.15;H,5.60; F,5.55%; I.R. 1749, 1738, 1716, 1708, 1679, 1508, 761, 697cm-1 [N.M.R. (in CDCl3): 0.81 and 1.08 (3H, two triplets, J=7 Hz), 1.80-2.04 and 2.46-2.80 (2H, two sets of multiplets), 3.53 and 3.68 (3H, two singlets), 4.58 and 4.62 (1H, two doublets, J=10 Hz), 5.39 and 5.42 (1H, two doublets, J=10 Hz), 6.96 (2H, t, J=8 Hz), 7.20- 7.60 (5H, m), 7.90-8.00 (2H, m)].
Reaction SMILES: [Li+].[BH4-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)[CH2:17]2)=O)=[CH:7][CH:6]=1)#[N:4]>C1(C)C=CC=CC=1.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:14][CH2:15][N:16]2[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][N:20]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:19]3)[CH2:23]2)=[CH:9][CH:10]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCC(=O)Nc3ccc(C#N)cc3)C2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCNc3ccc(C#N)cc3)C2)C1
Reaction time: 0.75 h
Yield: 10 %

Procedure:
LiBH4 (300 mg; 13.6 mmol) was added to a stirred solution of tert-butyl 7-{2-[(4-cyanophenyl)carbamoyl]ethyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.36 g; 3.41 mmol; see Example 22 above) in toluene (10 mL) and THF (5 mL) and the reaction mixture was stirred for 45 min. The solvents were removed and the residue partitioned between DCM and NaHCO3 (aq.). The organic layer was concentrated and subjected to column chromatography (DCM:MeOH; 9:1) to give the title compound in a 10% yield.
Reaction SMILES: [N-:1]=[C:2]=[O:3].O[CH2:5][CH:6]([CH2:8][OH:9])O>>[N-:1]=[C:2]=[O:3].[CH2:8]1[O:9][CH:6]1[CH3:5].[CH2:8]1[O:9][CH2:6]1
Reactant: OCC(O)CO
Agent: [N-]=C=O
Product: C1CO1
Product: CC1CO1

Procedure:
The organic polyisocyanate H (NCO content=28.1%) in the form of a prepolymer was prepared in a manner similar to that in the preparation of the organic polyisocyanate B, except that 16.0 parts of an isocyanate-modifying polyether polyol (functionality of the starting material=3; hydroxyl equivalent=1700; and EO content=95%) was reacted with polymethylene polyphenylisocyanate, which isocyanate-modifying polyether polyol was obtained by addition polymerization of propylene oxide and ethylene oxide as alkylene oxide to glycerin as a starting material. The thus obtained organic polyisocyanate H was deposited after it was left at the room temperature for two hours, so that this organic polyisocyanate H could not be used for forming the soft polyurethane foam described below.
Reaction SMILES: C1(C[C:8](C2C=NC=CC=2)=[O:9])C=CC=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:28][C:27](=[O:29])[NH:26][CH:25]([C:30]3[CH:35]=[C:34]([N+]([O-])=O)[C:33](O)=[C:32]([O:40]CC)[CH:31]=3)[C:24]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:19]C=1.NC(N)=[O:51].Cl>CCO>[OH:40][C:32]1[CH:31]=[C:30]([CH:25]2[C:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:23]([C:20]3[CH:19]=[N:16][CH:17]=[CH:22][CH:21]=3)[NH:28][C:27](=[O:29])[NH:26]2)[CH:35]=[CH:34][C:33]=1[C:8]([OH:9])=[O:51]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(N)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1cccnc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2cccnc2)=C(c2ccccc2)C(c2ccc(C(=O)O)c(O)c2)N1
Temperature: 40 °C
Reaction time: 5 h
Yield: 11.7 %

Procedure:
A mixture of 2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (220 mg, 1.1 mmol), methyl 4-formyl-2-hydroxybenzoate (Intermediate 84) (200 mg, 1.1 mmol), urea (198 mg, 3.3 mmol) and conc. HCl (0.2 mL) in EtOH (5 mL) was refluxed overnight. Solvent was removed in vacuo and the residue was taken up in a mixture of MeOH (10 mL) and aq. NaOH (2 M, 10 mL) and was stirred at 40° C. for 5 hours. The resulting mixture was cooled to room temperature, and then acidified with aq. HCl (2 M, 12 mL) to pH=5. Followed a standard aqueous/EtOAc workup and purified by prep-HPLC (0.1% TFA as additive) to give Compound 160 (50 mg, two steps yield 12%). 1H NMR (DMSO-d6, 400 MHz): δ 8.94 (s, 1H), 8.48 (d, J=3.6 Hz, 1H), 8.40 (s, 1H), 7.76 (m, 2H), 7.65 (s, 1H), 7.42-7.38 (m, 1H), 7.06-7.00 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.90-6.84 (m, 3H), 5.25 (s, 1H). MS (ESI): m/z 388.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Li][CH2:12]CCC.I[CH2:17][C:18]([O-:20])=[O:19].[Na+].S(Cl)(Cl)=O>C1COCC1.O>[CH3:12][O:20][C:18](=[O:19])[CH2:17][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCc1cccc(Cl)c1
Reactant: O=C([O-])CI
Reactant: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)COCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-ethanol (1.96 g, 12.51 mmol) in THF (55 ml) was added n-BuLi (8.8 ml, 1.6 M solution in hexane, 13.77 mmol) at −78° C. Then sodium iodoacetate (2.6 g, 12.51 mmol) was added and the mixture was allowed to warm to ambient temperature and was stirred overnight. The THF was then removed and 1 N HCl was added to the remaining residue to adjust the pH to 1. This mixture was extracted two times with dichloromethane and the combined extracts were dried (Na2SO4) and evaporated. The remaining red liquid was dissolved in MeOH (60 ml) and thionylchloride (1.56 ml, 21.5 mmol) was added dropwise at −15° C. The reaction mixture was then stirred for 1.5 h at ambient temperature. Then water was added and the mixture was extracted three times with ether. The combined extracts were washed with brine, dried (Na2SO4) and evaporated. The remaining residue was then purified by column chromatography (silica gel, heptane/ethyl acetate 95:5 to 88:12) to give the title compound (2.161 g, 9.45 mmol; 76%) as orange liquid. MS: m/e=229.2 [M+H+].
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:26])=[C:5]2[C:9](=[C:10]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=1[CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15]O)[C:8](=[O:25])[O:7][CH2:6]2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:15][C:14]([CH3:17])=[CH:13][CH2:12][C:11]1[C:10]([O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:24])[CH3:22])=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:25])=[C:4]([CH3:26])[C:3]=1[CH2:1][CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-bound triphenylphosphine (3 mmol/g, 152.1 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (151.3 mg, 0.456 mmol) was added and the solution was stirred at room temperature. After 2 hrs, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography to provide 58.0 mg (87%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20 (s, 3H), 2.70 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.94 (s, 2H), 4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m, 1H) ppm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:12][C:13]1([CH3:21])[O:20][C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1.N1CCCC1C(O)=O.[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:38]3[C:37]4[C:41](=[C:33]([CH2:32][S:31][CH3:30])[CH:34]=[CH:35][CH:36]=4)[NH:40][CH:39]=3)[CH:17]3[C:18](=[O:19])[O:20][C:13]([CH3:21])([CH3:12])[O:14][C:15]3=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc2sccc2c1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc4sccc4c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.02 g (5.66 mmol) of 1-benzothiophene-5-carbaldehyde, 0.82 g (5.66 mmol) of Meldrum's acid and 0.03 g (0.28 mmol) of D,L-proline were added to a solution of 1.00 g (5.66 mmol) of the compound from Example 8A in 8 ml of acetonitrile. The reaction mixture was stirred at RT overnight and then the solvent was removed in vacuo. Purification of the residue by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 1.73 g (71% purity, 47% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[H][H].Cl[CH:21]([CH3:25])[C:22]([NH2:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:12]=[C:11]([O:13][CH:21]([CH3:25])[C:22]([NH2:24])=[O:23])[CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc2oc3cc(Cl)ccc3c2c1
Reactant: CC(Cl)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Oc1ccc2oc3cc(Cl)ccc3c2c1)C(N)=O

Procedure:
21.7 g (0.1 mole) 7-chloro-2-hydroxydibenzofuran is dissolved in 200 ml of tetrahydrofuran. To this solution is added 5.2 g sodium hydride (50% dispersion in oil) which was prewashed in petroleum ether. After hydrogen evolution had ceased, the solution was brought to reflux and 11.2 g (0.1 mole) of 2-chloropropionamide was added. The mixture was allowed to reflux for 8 hours. The solvent was evaporated and the crude product was washed with dilute acid and crystallized from methanol to yield 14.5 g, m.p. 185°-187° C. This Example corresponds to Example 20 in Table I.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7](/[C:12](/[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)=[CH:13]/[C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1.[H][H]>CO.[Br-].[Zn+2].[Br-].[Pd]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1

Procedure:
Zinc bromide (20 mg) and 10% palladium-activated carbon (40 mg) were added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethenyl]pyrrolidin-2-one (100 mg) in methanol (3 mL), and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, after which the filtrate was concentrated under reduced pressure to give a crude product of (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethyl]pyrrolidin-2-one as an amorphous (120 mg).