Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([F:32])=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[C:21]([F:32])[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)c(F)cc1F
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c(F)cc1F
Yield: 69.3 %

Procedure:
A mixture of 0.217 g (1.12 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.3 g (1.12 mmol) of N-[5-(3-dimethylamino-acryloyl)-2,4-difluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 320 mg of N-{2,4-difluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 69%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][N:3]=1.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:10]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(OCC)c1ccc(Br)nc1
Yield: 92.2 %

Procedure:
In ethanol (60 mL) was dissolved 6-bromonicotinaldehyde (2.00 g, 10.8 mmol). Triethyl orthoformate (5.37 mL, 32.3 mmol) and p-toluenesulfonic acid monohydrate (102 mg, 0.538 mmol) were added and the mixture was refluxed for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 2-bromo-5-(diethoxymethyl)pyridine (2.59 g, 92% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:14])=[CH2:13])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:51][OH:52].CN([CH:56]=[O:57])C>C(OCC)(=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:51]([O:57][CH3:56])=[O:52])[CH:3]=2)[N:8]=1)([CH3:14])=[CH2:13]
Reactant: C=C(C)c1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc2cc(C(=O)OC)ccc2n1
Temperature: 80 °C
Yield: 82 %

Procedure:
A mixture of 6-bromo-2-isopropenylquinoline (200 mg, 1.45 mmol), palladium acetate (18.1 mg, 0.081 mmol), 1,3-bis(diphenylphosphino)propane (33 mg, 0.081 mmol), triethylamine (245 mg, 2.42 mmol. 0.337 ml) and methanol (1.03 g, 1.31 ml 32.2 mmol) in dry DMF (2.5 ml) was heated at 80° C. under carbon monoxide gas (balloon) overnight (15 hours). The mixture was diluted with ethyl acetate-toluene (8:1) (159 ml) and the precipitate was filtered through a pad of celite. The organic layer was washed with water (×2), brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (150 g) with hexane-ethyl acetate (15:1) to furnish the title compound (150 mg, 82%) as dark yellow solid. 1H NMR (270 MHz, CDCl3) δ 2.36 (3H, s), 3.99 (3H, s), 5.53-5.57 (1H, m), 5.98 (1H, s), 7.73-7.78 (1H, m), 8.08-8.31 (3H, m), 8.54-8.56 (1H, m). MS (ESI): m/z 228.21 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1CCCCO1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:14]1=[O:33]>>[O:33]=[C:14]1[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using chloroacetonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 155.8, 148.9, 142.232, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br)#[N:21]>>[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: N#Cc1ccccc1CBr
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccccc2C#N)c(=O)[nH]c1=O
Yield: 41.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (162 mg, yield: 41.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 17.7 g of benzenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 11.0 g of an end product. Melting point 140.0° C.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][N:10]2[CH2:12][CH2:13][N:14]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[CH3:29])[C:19]([N:30]([C:32](=[O:50])[C:33]([C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=4)([CH3:35])[CH3:34])[CH3:31])=[CH:18][N:17]=3)[CH2:15][CH:9]2[CH2:8][N:7]1[C:51](=[O:53])[CH3:52])(=O)C.[OH-].[Na+]>C1COCC1.O>[C:51]([N:7]1[C@@H:6]([CH2:5][OH:4])[CH2:11][N:10]2[CH2:12][CH2:13][N:14]([C:16]3[N:17]=[CH:18][C:19]([N:30]([CH3:31])[C:32](=[O:50])[C:33]([C:36]4[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=4)([CH3:34])[CH3:35])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[CH3:29])[CH:21]=3)[CH2:15][CH:9]2[CH2:8]1)(=[O:53])[CH3:52]
Reactant: CC(=O)OC[C@H]1CN2CCN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CC2CN1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CC2CN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CCN2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(3R)-2-acetyl-8-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl}methyl acetate (D97, 27 mg, 0.0472 mmol) in 2 mL of THF and 0.5 mL of water was added 1M NaOH (1 mL) and the resulting solution was stirred at room temperature for 30 min. It was checked by UPLC/MS, which showed a peak for the expected product at 0.76 min. (m/z=710 (M+1), 355 (M+2)/2). The target compound was isolated by SCX, obtaining 21 mg of the title compound.
Reaction SMILES: C1([N:6]([CH3:32])[C:7]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])CCCC1.[CH3:33]O.O1[CH2:39][CH2:38][CH2:37][CH2:36]1.O.[OH-].[Li+]>O>[CH:36]1([CH2:32][NH:6][C:7]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:33][CH2:39][CH2:38][CH2:37]1
Reactant: CO
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(CC(=O)N(C)C4CCCC4)cc32)c(OC)c1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1ccc2ccc(CC(=O)NCC3CCCC3)cc21
Reaction time: 6 h
Yield: 54 %

Procedure:
A solution of methyl 4-[6-(N-cyclopentyl-methylcarbamoylmethyl)indol-1-ylmethyl]-3-methoxybenzoate (1.34 g) in a combination of methanol (7.5 ml), tetrahydrofuran (7.5 ml), and water (3 ml) was treated with lithium hydroxide monohydrate (0.78 g). The mixture was stirred for 6 hr and then evaporated to remove the organic solvents. The resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The white precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.70 g, 54%) as a white powder; mp 188°-189°.
Reaction SMILES: [CH3:1]/[C:2](/N)=[CH:3]\[C:4]#[N:5].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][NH2:16])[CH:12]=[CH:13][CH:14]=1>Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:1])=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: C/C(N)=C\C#N
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: O
Product: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Yield: 20.1 %

Procedure:
(see, e.g., Ganesan, A., et al., Journal of Organic Chemistry 1993, 58, 6155-6157). A solution of 3-aminocrotonitrile (mixture of cis and trans) (1.50 g, 17.5 mmol) and 3-chlorophenylhydrazine hydrochloride (3.0 g, 16.2 mmol) in 25 mL of 1N HCl was heated to reflux for 3 h under nitrogen. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was recrystallized from hot iPrOH to give the title compound (677 mg, 20%) as a beige fluffy solid. 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.28 (d, J=9.5 Hz, 1H), 5.46 (s, 1H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 149.95, 145.30, 139.87, 135.05, 130.32, 126.86, 123.67, 121.28, 91.41, 13.89.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]([N:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]2)=[O:9])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A sample of 4-pyridinecarboxylic acid (1.32 g, 10.7 mmol) was dissolved in 50 mL of CH2Cl2. To this solution under N2 was added N-methylmorpholine (1.21 mL, 11.0 mmol) before it was cooled to -78° C. and isobutylchloroformate (1.39 mL, 10.7 mmol) was added. The reaction was allowed to warm to 0° C. and stirred at this temperature for 30 minutes before it was cooled again to -78° C. and t-butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 18 hours. All solvent was removed under reduced pressure to give a residue that was dissolved in EtOAc, washed with saturated NaHCO3 and brine, and dried (Na2SO4). After all solvent was removed in vacuo, the residue was chromatographed to generate 1.3 g of the title compound.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CCCCCC>[C:2]([N:6]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:7][C:17](=[O:18])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)N(NC(=O)Cc1ccccc1)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (2.0 g, 0.016M) in toluene (30 ml) was added 50% sodium hydroxide (1.3 g, 0.016M). After 15 minutes, the mixture was cooled to 5° C. and phenylacetyl chloride (2.4 g, 0.016M) and 50% sodium hydroxide (1.3 g, 0.016M) were added separately and simultaneously so as to maintain the reaction temperature below 10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with hexane and the solid product isolated by filtration. This product (3.2 g, 0.015M) was dissolved in a stirred mixture of toluene (30 ml) and cooled on ice. To this mixture was added benzoylchloride (2.2 g, 0.016M) and 50% sodium hydroxide (1.3 g, 0.016M) simultaneously. After addition, the mixture was stirred for 1/2 hour, diluted with hexane and the solid product, N'-t-butyl-N-phenylacetyl-N'-benzoylhydrazine, isolated by filtration.
Reaction SMILES: C[Mg]Cl.CON(C)[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:8].[C:25](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:8])[CH3:25]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)SCC2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔvAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.00 (c=1.39, EtOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=O.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:12])[O:11][CH2:14][C:15]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)c(F)c3)C(=O)OC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHEMICAL) (10 g) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone Example 9, Step 1 ) (17.3 g) in acetonitrile (200 mL) at room temperature was added slowly triethylamine (20.2 mL). After 1 h at room temperature, the mixture was cooled in an ice bath and treated with 17.4 mL of DBU. After 2 h at 0° C., the mixture was treated with 200 mL of 1N HCl and the product was extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was applied on top of a silica gel plug (sintered glass funnel) eluted with 75% EtOAc/hexane, giving after evaporation of the solvent and swish in ethyl acetate, 10 g of the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)C=C.C(OCC)(=O)C.C(N(CC)[C:22]1[CH:27]=CC=C[CH:23]=1)C>>[CH2:27]([C:10]1[C:9]([CH3:11])=[CH:8][C:7]([CH3:12])=[CH:6][C:5]=1[OH:4])[CH:22]=[CH2:23]
Reactant: C=CCOc1cc(C)cc(C)c1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(C)cc(C)cc1O
Temperature: 210 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of 1-(allyloxy)-3,5-dimethylbenzene obtained in Reference Example 214 (1.0 g, 6.2 mmol) in N,N-diethylaniline (4 mL) was stirred under argon atmosphere at 210° C. for 5 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with hydrochloric acid and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 7:3) to obtain 938 mg (yield 94%) of the title compound. Oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:13][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1nc(C(Cl)(Cl)Cl)nc(C)c1Cl
Yield: 80.8 %

Procedure:
To a solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.0 g (0.02 mole) triethylamine, and 100 ml ether was added 2.2 g (0.02 mole) ethyl chloroformate. An immediate reaction ensued and a precipitate formed. After refluxing 2 hours longer the mixture was filtered, and the filtrate was washed with aqueous potassium carbonate and then with water. Rotary evaporation yielded 5.4 g residue which was recrystallized from ligroin to give 4.6 g (69% yield) of pure product (mp 43.5°-44.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][CH2:8]CO>C1(C)C=CC=CC=1>[ClH:6].[Cl:6][CH2:7][CH2:8][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: OCCCCl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCCN1CCCC1
Temperature: 25 °C
Yield: 123.5 %

Procedure:
165 ml (2 mol) of tetrahydropyrrole, 67 ml (1 mol) of 3-chloropropanol and 200 ml toluene were added successively into a reaction flask. The mixture was heated to the reflux temperature and reacted for 3 h. After cooling to room temperature, a solid was separated out. The solid was filtered by sucking, and the filter cake was washed with 20 ml toluene. The temperature of the filtrate was controlled at about 75° C., and 200 ml thionyl chloride was added dropwise. After refluxing for 2 h, the mixture was cooled to room temperature and then concentrated to dry in a reduce pressure. The residue was recrystallized with absolute ethyl alcohol to obtain 105 g white solid with the yield of 62.3%. m.p. 169-173° C.
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](C(=O)C)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.ClCCl>[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:10][C:8](=[O:9])[CH3:4])=[CH:31][CH:32]=2)=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Metachloroperbenzoic acid (0.23 g) was added to a solution of 1-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.36 g) in chloroform (25 mL) while stirring at room temperature. Stirring was continued overnight then the reaction was diluted with dichloromethane, washed with saturated aqueous sodium thiosulfate, dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was diluted with methanol (5 mL) and saturated aqueous sodium bicarbonate (5 mL) then stirred overnight at room temperature. The methanol was removed on a rotary evaporator and the pH of the residue was adjusted to 7-8 then extracted with dichloromethane (3×30 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield 0.4 g of crude product, which was purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (117 mg), 1H NMR (CDCl3, 300.00 MHz): 8.01-7.93 (m, 2H), 7.42-7.21 (m, 7H), 7.06-6.97 (m, 4H), 3.87 (s, 2H), 3.02-2.94 (m, 4H), 2.61 (s, 3H); m/z=361.85(M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.[Na]>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2
Reactant: CC(C)C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2CC(C)C

Procedure:
To the material isolated in Step A in 2 mL of dichloromethane was added 0.041 mL (0.90 mmol) of iso-butyraldehyde, followed by 0.026 mL (0.45 mmol) of acetic acid and 0.10 g (0.45 mmol) of sodium tracetoxyborohydride. After 16 h at ambient temperature the reaction was diluted with 30 mL of dichloromethane and washed twice with equal volumes of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase BPLC afforded the tide compound.