Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl.[CH3:32][C@@H:33]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C@H:34]([NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:35](ON1C(=O)CCC1=O)=[O:36].C(N(CC)CC)C>CN(C)C=O>[NH:45]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:34]([C:35]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:36])[C@@H:33]([CH3:32])[O:56][C:57]([CH3:59])([CH3:60])[CH3:58]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
9.3 g of H-Gln-Asn-Phe-OCH3 hydrochloride and 11.9 g of Z-Thr(tBu)-OSU are dissolved in 150 ml of dimethylformamide to form a clear solution. 2.85 ml of triethylamine in 10 ml of dimethylformamide are added and the batch is stirred for 21 hours at room temperature. The batch is then concentrated under reduced pressure and taken up in much ethylacetate+chloroform (9:1), and extracted with 2 × 200 ml of 5% citric acid and 1 × 100 ml of water. The insoluble precipitate is then filtered off, the filtrate extracted with 2 × 200 ml of 2N-sodium carbonate solution and 3 × 100 ml of water, dried over sodium sulfate, and evaporated. The residue is recrystallized, together with the filter residue mentioned above, from dimethylformamide+ether (1:1). Melting point, 237°- 241°C (decomp.); [α]20D = + 8° (c = 1% in dimethylformamide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7](=[S:29])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2OC)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=S)Nc2ccccc2OC)cc1
Yield: 153.2 %

Procedure:
4-Methoxy-2'-methoxybenzanilide (29.5 g) [Bull. Soc. Chim. France, 1964, (5), 924-935] was dissolved in 150 ml of toluene, and 25.6 g of Lawesson's reagent was added. The mixture was refluxed for 4.5 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with cyclohexane/ethyl acetate (7/1, v/v)] to give 26.5 g of 4-methoxy-2'-methoxybenzothioanilide.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH3:10])[C:9]([CH2:1][OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: Cc1ccccc1
Agent: [Na+]
Product: Cc1ccccc1CO

Procedure:
The preferred conditions are to dissolve 1 mole of alcohol (II) and 1.25 to 1.75 mole of ester (V) in which R4 is methyl in 25 to 35 parts by weight of toluene, referred to the quantity of (II) used. The solution is heated to 65°-75° C., 0.025 to 0.05 mole of sodium methylate is added, and the toluene-methanol azeotrope formed is distilled slowly for 1 to 2 hours. A further 0.0125 to 0.025 mole of sodium methylate is added and the solution is distilled for 30 minutes to 1 hour; this last operation is repeated once more. The products of the reaction are then isolated and purified by the aforesaid techniques.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([NH:30][CH3:29])=[O:27])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: CN
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Agent: Cl
Product: CNC(=O)c1cc(OC2CCOc3cc(F)cc(F)c32)c2nc(C)n(C)c2c1
Yield: 96 %

Procedure:
The title compound was prepared as a colorless amorphous in 96% yield (0.99 g) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (1.0 g, 2.7 mmol, STEP 2) and methanamine hydrochloride (0.54 g, 8.0 mmol) by the same manner in STEP 3 of Example 11.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (1.92 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml). 1 M pH 3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg. 67%) as a white powder. Recrystallization from methylene chloridediethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s,3,ArCh3) 3.03 (dd,1,J=3.0 and 17.0,HGβ), 3.16 (dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55 (dd,1,J=5.5 and 17.0, HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH2Ar), 7.35 (S,5,ArH0, 7.26 and 7.75 (two d's,4,J=9,ArH); UV (dioxane) 283 (E6600) and 277 (E6500) nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[C:3]=1[C:16]([F:19])([F:18])[F:17].[CH:20]#[C:21][CH3:22]>[Cu](I)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.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:20]#[C:21][CH3:22])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: C#CC
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC#Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Temperature: 50 °C
Yield: 65.4 %

Procedure:
A triethylamine (300 mL) solution of N-[4-chloro-2-iodo-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (Example 60A) (40 g, 98.6 mmol) was treated with 1-propyne (39.5 g, 988 mmol) followed by copper iodide (0.94 g, 4.9 mmol) and PdCl2(PPh3)2 (6.9 g, 9.8 mmol) in a Parr Bomb at −78° C. The reaction vessel was purged with N2, sealed and heated gradually to 50° C. overnight, then cooled to −78° C. The cooled mixture was diluted with Et2O and filtered through celite. The Et2O solution was washed with water once, brine once, and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-10% EtOAc-hexanes gradient) afforded the title compound as a yellow solid (20.5 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 2.22 (s, 3H), 1.33 (s, 9H); MS (ES) m/z 318 (M+1) and 320 (M+1, isotope).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39](O)[CH:38]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH:38]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@H]2CCN(c3ccc(C#N)cc3)C2)c1
Temperature: 4 °C

Procedure:
Dissolve 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile (188 mg, 1.00 mmol), triphenylphosphine (393 mg, 1.50 mmol) and 3-hydroxy-benzoic acid methyl ester (228 mg, 1.5 mmol) into 10 mL of dry THF under Ar. Cooled to 4° C. Add DEAD (0.26 mL, 1.50 mmol) in a drop-wise fashion. Stir mixture with warming to room temperature overnight. LC-MS analysis indicates the desired intermediate. Concentrate the mixture to dryness. Dissolve residue into CH2Cl2 and apply to a 2 mm SiO2 prep plate. Elute with 50% EtOAc/hexanes to give 113 mg of slightly impure 3-[(S)-1-(4-cyano-phenyl)-pyrrolidin-3-yloxy]-benzoic acid methyl ester.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd].C(OCC)C>[N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNc1cc(N2CCc3ccccc32)cc(C)n1
Agent: [Pd]
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CNc1cc(-n2ccc3ccccc32)cc(C)n1
Yield: 94.1 %

Procedure:
A mixture of 4-(1-indolinyl)-6-methyl-2-(methylamino)pyridine (0.45 g, 1.88 mM), 30% w/w palladium on charcoal (0.045 g) and diphenyl ether (10 ml) was heated under reflux for 45 minutes. The mixture was cooled. Diethyl ether (50 ml) was added and the catalyst removed by filtration through diatomaceous earth. The filter cake was washed with diethyl ether (50 ml). The filtrate and washings were concentrated under reduced pressure. The yellow solid obtained was further purified by flash chromatography (Merck 9385 silica, 100 g) eluting with diethyl ether to give 4-(1-indolyl)-6-methyl-2-methylaminopyridine as a solid (0.42 g, 90% yield), m.p. 156°-158° C.; NMR (CDCl3): 2.45(3H,s,CH3), 2.9-3.0(3H,d,NHCH3), 4.75-4.85(1H,br, NH), 6.3(1H,s, pyridine-3H), 6.6-6.7(2H, complex, pyridine-5H and indole-3H), 7.15-7.4(3H, complex, indole-2H and aromatic), 7.65-7.75(2H, complex, aromatic).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([F:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([F:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(F)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(F)cc2C1=O

Procedure:
The mixture of 10.0 g of N-(4-nitro-o-tolyl)-4-fluorophthalimide, 500 ml of ethyl acetate and 5 g of Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, and the residue recrystallized from ethanol, to yield the N-(4-amino-o-tolyl)-4-fluorophthalimide, melting at 180°-182°.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-2-but-3-enyloxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as light brown solid.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=2)[N:6]=1)(=O)C.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:4][C:5]1[N:14]=[C:13]([NH:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=2)[N:6]=1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(Br)ccc2n1
Reactant: NC1CCCCC1
Product: Nc1nc(NC2CCCCC2)c2cc(Br)ccc2n1
Yield: 93 %

Procedure:
This compound was synthesized from the product of example 11, i.e. 2-acetamido-6-bromo-4-(1,2,4-triazolyl)-quinazoline and cyclohexylamine in 93% yield, using the procedure described for example 17. The product was characterized by its mass spectrum as follows: MS (m/z): 321 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.6 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyridine (Method 91, 0.42 g, 2.18 mmol) and DIEA (0.46 ml, 2.61 mmol) in THF (10 ml) was added a 5-cyclopropyl-1H-pyrazol-3-amine (0.31 g, 2.50 mmol) solution in THF (5 ml) drop wise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 17 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=3:1) to give the title compound as a yellow solid (0.54 g, 89%). 1H NMR (400 MHz) 12.55 (s, 1H), 9.95 (s, 1H), 8.97 (s, 1H), 8.09 (s, 1H), 6.02 (d, J=2.0 Hz, 1H), 1.93 (m, 1H), 0.97 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 279; Found: [M+H]+ 280.
Reaction SMILES: Cl.[F:2][CH:3]([F:12])[C@H:4]1[CH2:9][NH:8][CH2:7][C@@H:6]([OH:10])[C@@H:5]1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([N:8]1[CH2:9][CH:4]([CH:3]([F:2])[F:12])[CH:5]([OH:11])[CH:6]([OH:10])[CH2:7]1)[CH2:20][CH2:21][CH3:22]
Reactant: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CC(O)C(O)C(C(F)F)C1
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 6 (0.30 g, 1.4 mmol), K2CO3 (0.48 g, 3.5 mmol) and BuBr (0.20 g, 1.4 mmol) was combined in DMF (10 mL) and heated overnight at 60° C. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc, washed with water and then brine and dried over Na2SO4. After filtration, the filtrate was evaporated in vacuo to give the crude product which was purified by chromatography (CH2Cl2/(9:1) MeOH/NH4OH) to give the title compound (0.25 g, 80%) as a colorless sirup. MH+=224. 1H NMR (DMSO-d6) 6.2 (t, 1H, J=57 Hz), 5.13 (d, 1H, ex), 4.91 (d, 1H, ex), 3.3 (m, 1H), 3.1 (m, 1H), 2.9 (m, 2H), 2.3 (m, 2H), 1.95 (m, 2H), 1.75 (t, 1H), 1.2-1.5 (2m, 4H), 0.9 (t, 3H).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([O:40][CH3:41])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([O:40][CH3:41])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 1.5 h

Procedure:
To 1.5 mL of methanol solution containing 0.182 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-methoxyquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
2,4-difluoroaniline (9.0 g, 69.71 mmol) and pyridine (5.6 mL, 69.71 mmol) were dissolved in dichloromethane (45 mL) and the solution was cooled to 0° C. A solution of cinnamoyl chloride (13.04 g, 76.7 mmol) dissolved in dichloromethane (45 mL) was added dropwise, and after the addition the reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 and the layers were separated. The organic layer was washed with 1 M HCl then dried over Na2SO4 and concentrated in vacuo to provide a white solid. The solid was slurried in dichloromethane (150 mL), stirred for 30 minutes, and then hexanes (150 mL) were added. After stirring several minutes, the white solids were collected by filtration, washed with dichloromethane and air-dried to provide 13.5 g of the desired product. MS APCI (−) m/z 258.0 (M−1) detected.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.O=C1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.CCCCCC>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCOCC1
Reactant: COC(c1ccccc1)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(C2OC3(CCOCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 11.1 g. of 2-bromobenzhydryl methyl ether in 23 ml. of tetrahydrofuran and 7 ml. of hexane is cooled to -50°C. and 22 ml. of butyllithium is introduced while maintaining the temperature below -50°C. The solution is stirred for 2 hours at -60° to -70°C. To the suspension is then added a solution of 5 g. of 4-oxo-tetrahydropyran in 5 ml. of tetrahydrofuran over a span of a few minutes. The mixture is stirred at -60°C. for 3 hours and at ambient temperature overnight. Ice-water is added, the organic layer is separated, the aqueous layer is extracted with methylene chloride and the combined organic solutions are dried over sodium sulfate. The solvent is removed under reduced pressure and subjected to column chromatography over alumina. Elution with benzene removes benzhydryl methyl ether, and the column is then eluted with diethyl ether. The solid obtained is heated at reflux in 60 ml. of glacial acetic acid, and then the solvent is removed under reduced pressure to leave a crystalline solid. This solid is recrystallized from hexane to give 1,2',3,3',5',6'-hexahydro-3-phenylspiro[isobenzofuran-1,4'-pyran] as colorless crystals, m.p. 132° - 134°C.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].Cl.[OH:11][CH:12]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]([OH:16])[C@H:13]1[NH2:14].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5]([NH:14][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[CH:12]=[O:11])=[O:6]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2,2,2-Trichloroethoxycarbonyl chloride (200 g, 0.944 mol) is added portionwise to a solution of D-glucosamine hydrochloride (v, 200 g, 0.927 mol) and NaHCO3 (200 g, 2.4 mol) in water (4 L) in a 10 L 3-neck round-bottom flask and the resulting mixture is mechanically stirred overnight at room temperature. The white precipitate that forms is collected by filtration using a 2 L fritted funnel washed with ether (2 L), and dried at high vacuum for 3 hours to give 297 g (90%) of 2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucose as a white solid (MW 354.57).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH2:16][C:15]([NH:14][CH:7]([CH3:6])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:26])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(C)CCCC(C)NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)CCCC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 56.1 %

Procedure:
Thiosemicarbazide (1.32 g, 14.5 mmol) was added to a solution of N-(1,5-dimethyl-hexyl)-4-oxo4-phenyl-butyramide (2.54 g, 87.9 mmol), prepared in the previous step, in 30 ml of methanol plus 2.4 ml of 1 N HCl plus 2.4 ml of water and the reaction stirred at room temperature for 48 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.95 g of an off-white solid foam. Purification of this foam by chromatography on silica gel (230-400 mesh) using 3:1 hexane-ethyl acetate and then 3:1 ethyl acetate-methylene chloride as the eluted gave the title compound (2.63 g, 82%) as a white foam, mp 58-65° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:10][C:9](=[O:11])[CH:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)C=Cc1ccc(O)cc1
Yield: 30.5 %

Procedure:
1-Phenylbut-1-en-3-one (58.4 g), and p-hydroxybenzaldehyde (48.8 g) are dissolved in ethanol (300 ml) and cooled to a temperature below 15° C., using an ice bath. A solution of sodium hydroxide (20 g) in water (80 ml) is added over 2 hours, the temperature of the mixture being kept below 15° C. This solution is then neutralised to pH 7 with dilute hydrochloric acid. An oily solid separates out, and this is filtered and washed with toluene to give 30.5 g of 1-(p-hydroxyphenyl)-5-phenylpenta-1,4-dien-3-one.