Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].O>CN(C)C=O>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(CC(=O)c2ccncc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=CN(C)C)C(=O)c2ccncc2)cc1

Procedure:
A solution of 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone (10.2 g) and dimethylformamide-dimethylacetal (20 cm3) in dry dimethylformamide (50 cm3) was stirred at 80° C. for 4 hours. The mixture was cooled, poured into water (500 cm3) and extracted with ethyl acetate (3×200 cm3). The combined extracts were washed with brine (100 cm3), dried (magnesium sulphate), filtered and concentrated to give a yellow solid. The material was washed well with diethyl ether-hexane (1:9; 2×100 cm3) and dried in vacuo to give 3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one as a beige solid (7.7 g; 60%). δH (250 MHz; CDCl3) 2.78 [6 H, broad s, N(CH3)2], 3.79 (3 H, s, OCH3), 6.79 (2 H, d, J 9, methoxyphenyl H-2), 7.04 (2 H, d, J 9, methoxyphenyl H-3), 7.24 (2 H, d, J 6, pyridyl H-3) 7.40 (1 H, s, C═CH) and 8.51 (2 H, d, J 6, pyridyl H-2).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].N([O-])=O.[Na+].[Na+].[I-:22].CCO>O.Cl>[I:22][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)c1ccc2ccc(I)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of sodium 7-aminonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 4.06 mmol) in water (6.0 mL) and conc. HCl (2.0 mL) was cooled to 0° C. A premixed solution of NaNO2 (280 mg, 4.06 mmol) in water (2.0 mL) was added slowly, maintaining the temperature close to 0° C. The reaction mixture was stirred at 0° C. for 1 h. A solution of NaI (609 mg g, 4.06 mmol) in water (3.0 mL) and conc. HCl (1.0 mL) was then added dropwise over 30 min, maintaining a temperature close to 0° C. The reaction mixture was stirred at room temperature for 2 h and then heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature, treated with EtOH (10.0 mL) and concentrated in vacuo. EtOH (10 mL) was added and the mixture was filtered to give the title compound (1.07 g, 79%) as a tan solid. 1H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.09 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.80-7.68 (m, 3H); MS(ESI−) m/z 333.2 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[C:7]([O:13][CH2:14][CH3:15])[N:6]=1)=[O:4].[Li+].[OH-].Cl>C(O)C.O>[NH2:11][C:9]1[C:8]([Cl:12])=[C:7]([O:13][CH2:14][CH3:15])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: CCOc1nc(C(=O)OC)cc(N)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(C(=O)O)cc(N)c1Cl
Yield: 70 %

Procedure:
This material from step A was treated with LiOH in ethanol/water (5:3, 1 M, 2 mL) at ambient temperature for 2 h. HCl(aq) was added after 30 min to adjust pH value to 1. The precipitates were collected to afford the titled compound (130 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1c[nH]nc1C
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(CCc2ccccc2)c1C
Temperature: 20 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (30 mL) was added (bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20° C. for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column: Dsisol, 10 μM, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid)-water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven: 20° C.; flow rate: 50 mL/minute, wavelength: 214 nm) to give crude methyl 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylate (177 mg, 36%). The product was used for the next step directly. LRMS (M+H+) m/z: calcd. 244.12. found 244.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CNc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)c1ccccc1
Yield: 53 %

Procedure:
According to GWM, 0.011 mol (=1.20 ml) of N-methylaniline and 0.011 mol (=1.00 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:3) as eluent, the product N-methyl-N-phenylethylaniline being obtained as a yellow liquid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([NH:17][C@@H:18]([C:20]([NH:22][C@H:23]3[CH2:27][C:26](=[O:28])[O:25][C@@H:24]3[O:29]CC3C=CC=CC=3)=[O:21])[CH3:19])=[O:16])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([CH:24]=[O:29])[CH2:27][C:26]([OH:28])=[O:25])=[O:21])[CH3:19])=[O:16])[NH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)N[C@H](C=O)CC(=O)O
Reaction time: 5 h
Yield: 52.7 %

Procedure:
A mixture of (2R,S,3S)N2 -[4-(3-Phenylpropyl)imidazole-2-carbonyl]-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-alaninamide (0.93 g, 1.90 mmol) and 10% palladium on activated carbon (0.93 g) in methanol (100 ml) was stirred under a hydrogen atmosphere for 5 h. The resulting mixture was filtered and concentrated to yield a colorless glass. Recrystallization from methanol-diethyl ether afforded 401 mg (53%) of 20d as a colorless solid: mp. 94°-96° C.; [α]D27 +16.4° (c 0.5, MeOH); IR (KBr) 3300, 3287, 1786, 1732, 1659, 1651, 1532, 1451; 1H NMR(CD3OD) δ 7.19 (5H, m), 6.91 (1H, s), 4.60-4.46 (2H, m), 4.27 (1H, m), 2.63 (4H, m), 2.75-2.40 (2H, m), 1.96 (2H, m), 1.44 (3H, d, J=7.0).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(-c2ccncc2)cc1

Procedure:
Part A. A solution of 4-bromopyridine hydrochloride (1.0 g, 6.3 mmol) in acetonitrile-water (50 mL/20 mL) is treated with 4-isopropylbenzeneboronic acid (1.04 g, 6.3 mmol) and sodium carbonate (2.1 g, 25.2 mmol). The mixture is degassed twice, and a catalytic quantity of tetrakis(triphenylphosphine)palladium is added. The mixture is heated to reflux for 12 h., then cooled and poured into water (50 mL). The mixture is filtered and extracted with ethyl acetate (3×50 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford 1.01 g of sufficiently pure product, 4-(4-isopropyl-phenyl)-pyridine.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[O-:13]Cl=O.[Na+].Cl>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]([OH:13])=[O:7])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C(=O)O)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (78.8 g, 0.48 mol) in DMSO (585 mL), a solution of NaH2PO4 dihydrate (17.3 g, 0.144 mol) in water (160 mL) is added over a period of 13 min. The mixture is stirred at rt an a solution of NaClO2 (65.17 g, 0.577 mol) in water (160 mL) is added while the mixture is cooled with an ice-bath. The mixture is stirred for 1 h before a second portion of NaClO2 (43.44 g, 0.480 mol) in water (100 mL) is added while the temperature is kept between 25 and 40° C. with an ice-bath. The yellow suspension is stirred at rt for 24 h before it is acidified with 32% aq. HCl to pH 2-3. The mixture is extracted with TBME (250 mL), the org. extract is washed with water, and the washings are extracted back with TBME. The solvent of the combined org. extracts is evaporated to give crude 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6](=[O:19])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:8]=1)([CH3:3])[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:8][N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:16])([F:18])[F:17])[C:6]2=[O:19])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CC(C)c1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CC(C)c1cn(-c2ccccc2C(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isopropyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 19, 50 mg) by alkylation with bromomethylcyclopropane (25 mg). 3-Cyclopropylmethyl-4-isopropyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (11 mg). MS (ESI): 325.3 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].S(=O)(=O)(O)[OH:14]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([NH2:12])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#CCc1nc2ccccc2s1
Product: NC(=O)Cc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(Benzothiazol-2-yl)acetonitrile (2.05 g, 12 mmol) was added in portions to stirred concentrated sulfuric acid (5 mL) over 10 min. The mixture was stirred for 4 hr, then poured over ice/water. The precipitate that formed was extracted into EA and washed with brine, then the organic phase was dried over magnesium sulfate and the solvent removed under vacuum to give 2-(benzothiazol-2-yl)acetamide (1.02 g) as an orange solid.
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:47])[CH:44]([CH3:46])[CH3:45])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-valine benzyl ester hydrochloride (244 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (256 mg, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])[CH3:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(O)cc1C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 18 g (100 mmol) of 4-hydroxy-2-methyl-benzoic acid ethyl ester (prepared according to Sen, et. al. (1987), Indian J. Chem. Sec B, 26: 679-682), 10.2 g (150 mmol) of imidazole, and 17.2 g (115 mmol) of tert-butyldimethylsilyl chloride in 110 mL of anhydrous DMF was stirred for 24 hours at room temperature. The reaction was diluted with water and extracted with ethyl acetate. The organic fraction was washed with water, 0.1 N HCl, and brine, then dried over anhydrous magnesium sulfate and concentrated to 28.8 g of the title compound; MS (ESI+): m/z 295.5 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=[O:14])=[C:5]2[OH:18].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[OH:18]
Reactant: CCOC(=O)c1cnc2c(C)cc(Br)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)cc2c(O)c(C(=O)O)cnc12
Yield: 100.1 %

Procedure:
A mixture of ethyl 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate (1.89 g, 6.09 mmol) and 6 N NaOH (1.22 g, 30.45 mmol, 5.1 mL) in ethanol (30 mL) was heated at reflux for 2.0 h and concentrated in vacuo. The residue was diluted with water and acidified with 6 N HCl to pH 4. The resulting solid was filtered, washed with water and diethyl ether, and dried overnight in a Buchner funnel to give the title compound (1.72 g, 99%) as a tan solid. MS (ES)+ m/e 282 [M+H].
Reaction SMILES: C([OH:3])C.[O:4]=[C:5]1[CH2:13][C:12]2[C:7](=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6]1.[OH-].[Na+:22]>O>[NH2:6][C:7]1[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:5]([O-:3])=[O:4].[Na+:22]
Reactant: CCO
Reactant: O=C1Cc2cccc(Oc3ccccc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccc1

Procedure:
To a mixture of ethanol (50 ml.) and water (50 ml.) were added 2-oxo-7-phenoxyindoline (20.7 g.) and sodium hydroxide (14.8 g.). The mixture was refluxed under heating for 30 hours with stirring. After cooling, the reaction mixture was filtered and ethanol was distilled off from the filtrate. The remaining aqueous solution was adjusted to pH 8.3 with conc. hydrochloric acid and filtered. The filtrate was washed with diethyl ether and concentrated to dryness under reduced pressure. The residue was dissolved in ethanol and filtered, and the filtrate was evaporated under reduced pressure. The oily residue was crystallized with ethyl acetate. The resultant substance (17.8 g.) was dissolved in water and filtered. The filtrate was lyophilized to give powdery captioned compound (17.6 g.). mp 205° to 208° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH2:17].CCN(CC)CC>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:4]
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
Under N2 at −75° C., trifluoroacetic acid was added to a stirring solution of 2,3-dihydro-1H-inden-2-amine (HCl salt, 8.0 g, 47.2 mmol), Et3N (14.9 ml, 106.7 mmol) and THF (160 ml). After the solution was allowed to warm up to rt, it was partitioned between H2O and DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexanes:Et2O (1:1) to obtain the product as a white solid (8.9 g, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 4H), 6.50 (s, 1H), 4.81-4.74 (m, 1H), 3.38 (dd, J=16.4, 7.1 Hz, 2H), 2.89 (dd, J=16.3, 4.2 Hz, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:9]=1.O=S(Cl)Cl>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[C:1](=[O:7])[CH2:2][CH2:3][C:4]3=[O:6])=[CH:8][CH:9]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CCC(=O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of succinic anhydride (250 mg, 2.50 mmol) and 4-amino-4′-chloro diphenylether (500 mg, 2.27 mml) in toluene is heated to 110° C. for 14 h. and cooled down to room temperature. SOCl2 (1.5 mL) is added into the mixture and stirred at room temperature for 8 h. After the solvent is removed under vacuum, the residue is treated with saturated NaHCO3 aqueous solution (20 mL) and extracted with CHCl3 (3×50 mL). The combined organic layer is washed with brine and dried (MgSO4). After filtering the drying agent, the filtrate is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 30%˜80%) to provide 1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione as white solid (570 mg, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][CH2:18][CH:20]2[CH2:21][O:22]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CC(OCC2CO2)C1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
To a solution of 8 (30 g, 0.15 mol) in DMSO (250 mL) was slowly added a solution of NaOH (9.9 g, 0.25 mol) in water (195 mL) at 15-25° C. Epichlorohydrin (93.8 g, 1.01 mol) was added and the mixture was stirred at 20-25° C. for 24 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 3:2, yielding 9 as a clear oil (32.1 g, 84%). 1H NMR (300 MHz, CDCl3): δ 2.60 (1H, dd, J=4.8, 2.6 Hz), 2.81 (1H, dd, J=4.9, 4.2 Hz), 3.09-3.16 (1H, m), 3.25 (1H, dd, J=11.4, 6.2 Hz), 3.68 (1H, dd, J=11.5, 2.5 Hz), 3.89-3.97 (2H, m), 4.15-4.24 (2H, m), 4.29-4.37 (1H, m), 5.09 (2H, s), 7.28-7.36 (5H, m); 13C NMR (75 MHz, CDCl3): δ 44.2, 50.4, 56.7, 56.9, 66.7, 68.6, 70.0, 128.0, 128.1, 128.5, 136.6, 156.5; IR: (film) 2951, 1709, 1420 cm−1; ES-HRMS m/z: (M++1H) calcd. for C14H18NO4 264.1230. found 264.1230.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH3:7])=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[OH:1]
Reactant: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)C(=O)c1ccccc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 378.6 %

Procedure:
To a solution of tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 0.68 mmol) in CH2Cl2 (5 mL) at 0° C. was added trifluoroacetic acid (1.8 mL, 23.4 mmol). The mixture was stirred (0° C., 16 h), concentrated under reduced pressure and neutralized with saturated NH3 in CH3OH. The mixture was concentrated under reduced pressure to afford N-(2-aminoethyl)-2-hydroxy-N-methylbenzamide as a colorless oil (0.5 g). This compound was used in the next step without further purification. Mass calculated for C10H14N2O2=194.23. found: [M+H]+=195.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[N:20]([NH2:21])[CH:19]=[N:18][N:17]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:11]=[N:21][N:20]3[CH:19]=[N:18][N:17]=[C:16]3[N:15]=2)[CH:4]=1
Reactant: Nc1nncn1N
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cnn3cnnc3n2)c1

Procedure:
A solution of 12.5 g. of m-trifluoromethylphenylglyoxal, 7.69 g. of 3,4-diamino-4H-1,2,4-triazole and 4.67 g. of sodium acetate in 120 ml. of 67% acetic acid is reacted as described in Example 4, giving the desired product as a yellow solid, m.p. 288°-290° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])C(=O)OC(C)(C)C)=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:6]([NH:7][CH2:15][CH3:16])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 1 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-necked round bottom flask equipped with a magnetic stir bar was added a solution of tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)carbamate (21 g, 65.1 mmol) in 1.4-dioxane (35 mL). This pale yellow solution was placed into an ice bath and cooled to 1° C. A solution of 4M HCl in dioxane (65 mL, 260 mmol) was added in one portion. After stirring for 20 minutes, the ice bath was removed and the suspension was stirred further at ambient temperature for 16 hours. The reaction was diluted with 200 mL of ethyl ether and the solid was filtered and washed with ether and placed in a vacuum oven at 40° C. for 18 hours. The title compound was isolated as a pale yellow solid (18.2 g, 95%): 1H NMR (400 MHz, MeOD) δ 9.52 (d, J=2.5 Hz, 1H), 9.17 (s, 1H), 9.14 (ddd, J=8.7, 2.5, 1.1 Hz, 1H), 8.93 (ddd, J=5.7, 1.1, 0.6 Hz, 1H), 8.31 (ddd, J=8.7, 5.7, 0.5 Hz, 1H), 3.58 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.3 Hz, 3H); ESIMS m/z 223 ([M+H]+).