Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:16]1([CH2:22][C:23](=[NH:26])[NH:24]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:16]1([CH2:22][C:23]2[N:26]=[C:13]([CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:15][N:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: N=C(CC1CCCCC1)NO
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(CC3CCCCC3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 0.39 g (1.88 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.333 g (2.00 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of 2-cyclohexyl-N-hydroxyacetimidamide (compound of Example 44; 0.6 g, 3.8 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mass was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COc1ccccc1[Zn+]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(C(=O)c2ccccc2OC)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.11 g; 5.4 mmol) was heated to reflux in the presence of 30 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-methoxyphenylzinc iodide (11.0 mL; 5.4 mmol), tetrakis(triphenylphospine)palladium (0) (90 mg; 0.08 mmol) in 2.5 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 900 mg of title compound. (64% yield)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>C1(C)C=CC=CC=1.CCOCC>[F:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2](=[O:3])[CH2:1][C:13]([CH3:15])([CH3:12])[O:11]2)=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)CC(=O)c2ccc(F)cc2O1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-hydroxyacetophenone (Aldrich, 1.54 g, 10 mmol), acetone (0.95 mL, 12.9 mmol), and pyrrolidine (0.83 mL, 9.94 mmol) was stirred in 3 mL toluene at room temperature for 1 h and at reflux (Dean-Stark trap) for 4 hours. After cooling to room temperature, the mixture was diluted with ether (30 mL) and was washed with 2N HCl (10 mL) and H2O (10 mL). Drying over Na2SO4 and evaporation of volatiles in vacuo afforded the crude title compound, which was used without further purification.
Reaction SMILES: [Li]CCCC.Br[C:7](Br)=[CH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1>C1COCC1>[C:27]1([C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]2[CH:13]=[C:9]([C:8]#[CH:7])[N:10]=[CH:11]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrC(Br)=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
n-BuLi (0.192 ml, 0.48 mmol) was added to a solution of 4-(2,2-dibromovinyl)-1-(triphenylmethyl)imidazole (108 mg, 0.22 mmol) in THF (5 ml) at −78° C. under N2. The reaction mixture was quenched by the addition of saturated ammonium chloride (50 ml) and extracted with ethyl acetate (75 ml). The ethyl acetate layer was washed with water (50 ml), separated, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography gave 2[1-triphenylmethyl-1H-imidazol-4yl]ethyne, which was deprotected with 2N HCL to give 18 mg of final product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH2:27]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)nc1C
Yield: 25.5 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (579 mg) described in Preparation Example 176 and 5,5-dimethyloxazolidin-2-one (153 mg) described in Preparation Example 43, the title compound (143 mg) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH:2]([CH3:4])[CH3:3].[CH2:11]([CH:13]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14]OC(=O)C(C)=C)[CH3:12].[CH3:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29]>>[CH2:1]([O:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH:2]([CH3:4])[CH3:3].[CH2:11]([CH:13]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH:8]=[C:7]([CH3:9])[C:6]([O-:5])=[O:10])[CH3:12].[CH3:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29]
Reactant: C=C(C)C(=O)OCC(CC)CCCC
Agent: C=C(C)C(=O)OCC(C)C
Agent: C=CC(=O)N(C)C
Product: CCCCC(CC)CC=C(C)C(=O)[O-]

Procedure:
A 60:30:10 (weight percent) isobutylmethacrylate/2-ethyl-hexylmethacrylate/N,N-dimethylacrylamide copolymer is prepared as follows. Isobutylmethacrylate, 2-ethylhexylmethacrylate, and N,N-dimethylacrylamide are weighed out (relative weight ratios of 60:30:10) and added to a four neck flask fitted with an argon sparge, mechanical stirrer, thermometer and condenser. Toluene is then added to the flask to get a final monomer concentration of 25.0 weight percent. The reaction flask is placed in a 60° C. water bath and the reaction mixture is sparged with argon for two hours while stirring. After two hours, azobisisobutyronitrile ("AIBN") is added to the reaction flask in an amount sufficient to get a final initiator concentration of 0.25 weight percent. The reaction is then stirred for two hours, after which time the reaction flask is removed from the water bath and the reaction mixture is poured into a polyethylene tray, air dried, and dried in a vacuum oven at 120° C. Optionally, after two hours of stirring, an additional 0.25% initiator is added and the reaction continued for an additional hour. It is then dried as stated. If it is desired to increase or decrease the polymer molecular weight this is done by altering the level of initiator used, or by adding a chain transfer agent (such as decanethiol) to the reaction mixture. The glass transition temperature of this copolymer is calculated to be approximately 38° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1Br)([CH3:9])([CH3:8])[CH3:7].C(I)C>C1COCC1>[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[CH2:1][CH3:2])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1Br
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc(C(=O)O)ccc1C(C)(C)C
Reaction time: 0.67 h

Procedure:
A solution of n-butyl lithium (1.6M in hexane, 2.67 mL, 4.27 mmol) was added dropwise to a solution of 4-tert-butyl-3-bromobenzoic acid (500 mg, 1.94 mmol) in THF at −78° C. whilst maintaining the temperature below −70° C. After 40 minutes, ethyl iodide (1.55 mL, 19.4 mmol) was added dropwise whilst maintaining the temperature below −65° C. After one hour at −70° C., the mixture was allowed to attain room temperature and stirred overnight The mixture was quenched by the addition of saturated ammonium chloride solution (30 mL) and extracted with ether (30 mL). The organic fraction was dried over magnesium sulphate and evaporated. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:36][C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:36][CH:35]([OH:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C1CC(c2cc(F)cc(F)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cc(F)cc(F)c1)O2

Procedure:
2-(3,5-Difluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 800 mg of 2-(3,5-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.21-7.17 (m, 3H), 6.88 (d, 1H, J 2.4 Hz), 6.64 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 2.4, 8.7 Hz), 5.47 (d, 1H, J 7.0 Hz), 5.17 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25](OC)=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36][O:37][CH3:38].CC[Mg+].[Br-].CCOCC>C1COCC1>[CH3:35][N:36]([O:37][CH3:38])[C:25](=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=1[CH2:22][CH2:21][C@@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:13]=[CH:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[OH:33]
Reactant: COC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CNOC
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON(C)C(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the hydroxy ester of Step 3 (4.519 g, 9.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.777 g, 28.5 mmol) in 95 mL of anhydrous THF at 0° C. was added dropwise 3M EtMgBr in Et2O (22 mL 66 mmol) over ≃40 min. The mixture was then stirred at 0° C. for 30 min. and poured into ice-cold saturated NH4Cl. The product was extracted in EtOAc, dried over Na2SO4, and concentrated to yield the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:27]([OH:39])[CH2:26][C:25]2=[O:40])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:27]([OH:39])[CH2:26][CH:25]2[OH:40])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C)(O)CS[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CS[C@H]1[C@H](O)CC(O)[C@@H]1CCCCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 1.3 g. of 11α,15-dihydroxy-15-methyl-9-oxo-13-thiaprostanoic acid p-benzoylaminophenyl ester, dissolved in 40 ml. of dry THF was added to a suspension of 3.3 g. of LiAl(O-tert.--C4H9)3H in 25 ml. of dry THF. The solution was allowed to stand for 1 hour at room temperature; then poured into 90 ml. of ice-cold 1 N HCl; and extracted with CHCl3. The organic phase was washed with water and dried over NaSO4. The solvent was distilled off. After chromatographic purification of the residue (silica gel/ethyl acetate), 9,11α,15-trihydroxy-15-methyl-13-thiaprostanoic acid p-benzoylaminophenyl ester was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].ClC1C=C(C=CC=1Cl)CC1CCN(C[C@H](N)C(C)C)CC1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:55]=[CH:56][C:57]=1[Cl:58])[CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([NH2:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][CH2:43]1>>[Cl:37][C:38]1[CH:39]=[C:40]([CH:55]=[CH:56][C:57]=1[Cl:58])[CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([NH:54][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:15])[C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:47]1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: CC(C)(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(C)[C@@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Product: COc1cc(NC(=O)N[C@@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)(C)C)cc(OC)c1OC

Procedure:
Proceeding as described in Example 13 above, but substituting 3-methoxyphenylisocyanate with 3,4,5-trimethoxyphenylisocyanate and 1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropylamine with 1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropylamine gave 1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2,2-dimethylpropyl}-3-(3,4,5-trimethoxyphenyl)urea.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[C:16]([Cl:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (127 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-28, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1cc(N2CCOCC2)nc(-c2ccccc2)n1
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)c1
Yield: 9.1 %

Procedure:
A mixture of 4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol), m-anisidine (20 μl, 0.181 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 5 days. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (50 ml), which was washed with water (2×25 ml), aqueous saturated NaCl, and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo and isolated as a yellow solid (6 mg, 9%). 1H NMR (CDCl3): 8.40–8.37 (m, 2H), 7.46–7.43 (m, 3H), 7.31–7.25 (m, 2H), 7.00 (t, J=2.3 Hz, 1H), 6.91 (dd, J=1.7, 8.0 Hz, 1H), 6.70–6.67 (m, 2H), 3.83 (s, 3H), 3.81–3.63 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:12](#[N:14])[CH3:13].Cl>O1CCOCC1>[CH3:13][C:12]1[NH:14][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccsc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2sccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 2-aminothiophene-3-carboxylate (0.1 g, 0.64 mmol) and acetonitrile (50 μl, 0.95 mmol) in dioxane (3 ml) was added 4M HCl in dioxane (3 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alkaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (42 mg, 40%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[O:8]([C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccccc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-(phenoxy)-phenol provided the title compound. MS ESI+: m/z=270 [M+H]+.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)[C:14]=1[CH3:15])=[O:9])C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[C:14]([CH3:15])=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)=[N:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cn2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(C)C)cn1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Isopropylbromide (164 μl) was added to a suspension of 1-(5-hydroxypyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (333 mg) and potassium carbonate (558 mg) in N,N-dimethylformamide (1.5 ml) and stirred at 80° C. for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was reacted and treated in a similar manner as Reference Example 24(3) to give the titled compound (152 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:32])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]
Reactant: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Combine 4-[3-(2-chloro-4-fluoro-benzoylamino)-phenoxy]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (Preparation 78, 0.60 g, 1.31 mmol), toluene (20 mL), and p-toluenesulfonic acid monohydrate (2.5 g, 13.1 mmol), stir, and heat at 100° C. After 1 hr., cool to ambient temperature. Concentrate the reaction mixture. Partition the residue between ethyl acetate (100 mL) and 1M aqueous sodium hydroxide solution (50 mL). Separate the organic layer, wash with 1M aqueous sodium hydroxide solution (2×50 mL), wash with aqueous NaCl solution (50 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane to obtain the title compound (0.26 g, 55%). Mass spectrum: Obs. m/z 363.1289; Calc. m/z 363.1275; Analysis calculated for C19H21C12FN2O2.0.9H2O: C, 54.92; H, 5.53; N, 6.74. Found: C, 54.90; H, 5.36; N, 6.55. 1H NMR (CDCl3) of free base: 7.9 (bs, 1H), 7.8 (m, 1H), 7.4 (s, 1H), 7.2 (m, 3H), 7.1 (m, 2H), 6.7 (dd, 1H), 4.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.15 (m, 2H), 1.45 (m, 2H), 1.1 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([F:27])[CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(F)cc(F)c3)nc2n(CC)c1=O
Yield: 63 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.06 g (16.6 mmol) of 3,5-difluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.30 g (yield 63% of Compound 155 as pale yellow plates.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(N(CC)CC)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)(C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)CC>>[C:1]([NH:5][C:6](=[O:11])[CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)N
Product: CCC(=O)NC(C)(C)C
Yield: 95 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of tert-butylamine (11.3 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with propionyl chloride (8.9 mL, 100 mmol) afforded LEt,tBuH as white crystalline solid (12.27 g, 95%) upon sublimation at 55° C./0.05 Torr: mp 90-92° C.