Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])(=[O:23])[CH2:21][CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CC(O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]=1[NH:24][C:20](=[O:23])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc2C1Cc1ccccc1
Reactant: CCC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCC(=O)NC1=C(Cc2ccccc2)c2cc(Br)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In a three-necked flask equipped with a Dean-Stark apparatus, heating mantle and magnetic stirrer were charged 1-benzyl-7-bromo-3,4-dihydronaphthalen-2(1H)-one (23.50 g, 74.6 mmol), propionamide (13.62 g, 186 mmol) and 4-methylbenzenesulfonic acid (1.284 g, 7.46 mmol) followed by toluene (200 ml). The resulting solution was heated to reflux overnight and monitored by HPLC (<6% starting material remained). The reaction mixture was cooled to r.t. and a suspension formed. To the mixture was added IPA and the resulting suspension was cooled to 0° C., stirred at 0° C. for 2 hours and filtered. The filtrate was concentrated and the residue was suspended in IPA/EtOH (50 ml/50 ml) at 0° C. for 1 hr and filtered to give additional product as a white solid. HPLC analysis indicated that both crops have similar purity. The solids were combined and further dried to give 22.5 g product as white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[N:19]([CH3:23])[C:18]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH3:23])[C:18]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from 10.31 g of the thione of Example 9 upon heating with 38.15 ml of tri-n-butyl tin hydride and 1.16 g of azobisisobutyronitrile (AIBN) in 142 ml of toluene at reflux temperature for one hour. The product was isolated by adding water to the cooled reaction mixture, separating the layers, washing the organic layer with 1N hydrochloric acid and a saturated sodium chloride solution, drying over magnesium sulfate, concentrating in vacuo, and purifying the residue by chromatography over silica gel eluting with a 10-50% hexane in ethyl acetate gradient. The purified product had a melting point of 142°-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2].CO.[C:27](=O)([O-])O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([O:21][CH3:27])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To 72 mg of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]-thiepin-2-yl)-propionic acid were added 10 ml of a diazomethaneether solution and 1 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. To this was added acetic acid, and the mixture was made alkaline with a saturated sodium hydrogen carbonate solution and then extracted with benzene. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellow oil, which was chromatographed over 2 g of silica gel and eluted with chloroform, thereby obtaining 44 mg (yield: 57%) of methyl 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15]C)=[O:14])[NH:7]2.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[NH:7]2
Reactant: COC(=O)c1cc(=O)c2c(C)cc(C)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 85.2 %

Procedure:
Treatment of methyl 5,7-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (1 g) with sodium hydroxide (0.69 g), as described in Example 1c, gave 5,7-dimethyl-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (0.8 g), m.p. 285°-287° C., δ (360 MHz,DMSO-d6) 2.33 (3H, s, 7-Me), 2.75 (3H. s, 5-Me), 6.49 (1H, s, 3-H), 6.87 (1H, s, 6-H) and 7.55 (1H, s, 8-H). (Found: C, 66.53; H, 4.96; N, 6.72%. C12H11NO3 requires C, 66.35; H, 5.10; N,6. 45%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]C(C)(C)C)=[O:16])[N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCC2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCC2C(=O)O)cc1
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 1-benzyl-4-([4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate (0.34 g, 0.68 mmol) in dicloromethane (2 mL) at 0° C. was added trifluoroacetic acid (1.23 mL). After 2.5 h the reaction mixture was allowed to warm to 25° C. whereupon an additional 1 mL of trifluoroacetic acid was added. After 18 h the reaction mixture was concentrated in vacuo to provide 1-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a white powder.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([F:4])[CH3:3].[CH2:10]=[O:11]>C(O)C>[F:1][C:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][OH:11])[N:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cc[nH]n1
Reactant: C=O
Solvent: CCO
Product: CC(F)(F)c1ccn(CO)n1

Procedure:
To an ethanol solution (1.0 mL) of 3-(1,1-difluoroethyl)-1H-pyrazole (145 mg, 1.09 mmol) synthesized in Reference Synthesis Example 118, a formalin aqueous solution (1.0 mL) was added and the resultant mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22])[C:24]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:25]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: Cc1ccc(CNC(=O)C(C)C(=O)O)cc1
Product: Cc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1

Procedure:
The title compound, MS: m/e=441.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(4-methyl-benzyl)-malonamic acid.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[NH2:6])[CH2:3][CH2:2]1.F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][CH:5]([NH:6][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: NC(CC1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(CC2CC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
A mixture of 2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethanamine (90 mg, 0.30 mmol), methyl 6-fluoronicotinate (68.7 mg, 0.443 mmol) and potassium carbonate (122 mg, 0.885 mmol) in DMF (5 mL) was stirred for 12 h at 120° C. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by preparative TLC to give methyl 6-(2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinate (60 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.85-7.88 (m, 1H), 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.18 (d, J=8.8 Hz, 1H), 5.80 (br, 1H), 4.74-4.72 (m, 1H), 3.78 (s, 3H), 1.83-1.56 (m, 2H), 0.71-0.60 (m, 1H), 0.50-0.33 (m, 2H), 0.18-0.05 (m, 2H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>[Cl-].[Al+3].[Cl-].[Cl-].Cl>[F:9][C:10]([F:18])([F:17])[C:11]([C:6]1[CH:5]=[CH:4][C:3]([CH3:7])=[CH:2][C:1]=1[CH3:8])([OH:12])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Reaction time: 1 h
Yield: 89 %

Procedure:
A 1 L reactor was charged under nitrogen with 100.0 g (0.94 mol) of m-xylene and 6.3 g (0.047 mol/0.05 eq) of aluminum chloride, followed by adjusting the inside temperature to 10° C. Then, 164.2 g (0.99 mol/1.05 eq) of hexafluoroacetone was introduced in a temperature range of 10-25° C. After the introduction, stirring was conducted at room temperature for 1 hr. Then, 100 mL of 10% hydrochloric acid was added. The resulting aqueous layer was extracted two times with 40 mL of chloroform. The resulting organic layers were combined together, followed by removing water with anhydrous magnesium sulfate, filtration, concentration, and vacuum distillation, thereby obtaining 227.6 g of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-dimethylbenzene represented by the following formula. Upon this, purity was 95%, and yield was 84%.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Cl[CH2:13][CH2:14][OH:15].Cl>CO>[C:3]1([CH2:2][CH2:1][S:9][CH2:13][CH2:14][OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCl
Reactant: SCCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCSCCc1ccccc1
Reaction time: 6 h
Yield: 68.2 %

Procedure:
Phenethylmercaptan (2.0 g) and potassium hydroxide (0.81 g) in methanol (15 ml) were stirred together under nitrogen for 15 min. 2-Chloroethanol (2.33 g) was added and the solution stirred under nitrogen for 6 h. 2N hydrochloric acid was added to acidify the mixture to pH5, and the methanol evaporated in vacuo. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and separated. The aqueous phase was re-extracted with diethyl ether (100 ml) and the combined ethereal layers dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System F (3:1) gave the title compound (1.80 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.70
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][CH2:11][CH2:12][S:13][CH3:14])=[CH:8][CH:7]=1)([O-])=O>[Zn]>[CH3:14][S:13][CH2:12][CH2:11][NH:10][C:9]1[CH:15]=[CH:16][C:6]([NH2:3])=[CH:7][CH:8]=1
Reactant: CSCCNc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CSCCNc1ccc(N)cc1

Procedure:
0.8 g of ammonium chloride and 20 g of powdered zinc are added to 44 ml of aqueous-alcoholic solution (10% of water, 90% of alcohol). This mixture is brought to reflux with stirring, and 0.04 mole (8.5 g) of 4-nitro-N-[β-(methylthio)ethyl]aniline is added, the addition being regulated so as to maintain the reflux without heating. The decolorized reaction medium is filtered while boiling into a flask containing 8.5 ml of 36% strength hydrochloric acid. The expected product precipitates in the form of a dihydrochloride. It is dried under vacuum at 55° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1)([O-])=O.CN(C)C=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc([N+](=O)[O-])ccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Yield: 97.7 %

Procedure:
A mixture of 10.0 g of 3,7-dinitrodibenzothiophene S,S-dioxide, 180 ml of dimethylformamide, 20 ml of glacial acetic acid and 1.0 g of 5% palladium on carbon was hydrogenated in a Parr apparatus until hydrogen uptake ceased. The mixture was then filtered through diatomaceous earth, the filtrate poured into 1 liter of ice water, the solid collected by filtration, washed with ethanol and ether and dried at 110° C., giving 7.86 g of the desired product as a solid mp 320°-330° C.(dec.).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][N:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][NH:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=NCCN1CCc3ccccc3C1)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)C(NCCN1CCc3ccccc3C1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 96 (1.42 g, 4.07 mmol) in anhydrous dichloroethane (10 mL) were sequentially added acetic acid (267 mg, 4.48 mmol) and NaBH(OAc)3 (1.12 g, 5.29 mmol) under N2. The reaction was stirred at room temperature for 2 hours before it was quenched by slow addition of water (100 mL). The mixture was extracted with dichloromethane (100 mL) and the organic layer was sequentially washed with water (100 mL), saturated aq. NaHCO3 (100 mL), and water (100 mL). The residue, from drying (Na2SO4) and concentrating the organic layer, was chromatographed on silica gel (EtOAc to 5:1 EtOAc/CH3OH) to yield 97 as a brown oil (755 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
4-(2-Carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.9 mmol, according to the procedure described in J. Med. Chem., 41(14), 2492, 1998) was dissolved in THF (50 ml) and cooled down to 0° C. 2M Borane solution in THF (3.9 ml, 7.8 mmol) was added slowly and the mixture was stirred for 20 h at room temperature. Water was added and solvents were concentrated in vacuo. The residue was dissolved in EtOAC, basified with NaHCO3, washed with brine, dried and concentrated in vacuo to yield the title compound (938 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:14](O)=O>>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:14]1
Reactant: CNc1c(N)cnc2ccccc12
Reactant: O=CO
Product: Cn1cnc2cnc3ccccc3c21
Yield: 77 %

Procedure:
A solution of 2.92 g of 3-amino-4-methylaminoquinoline (V-2) in 20 ml of formic acid was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between chloroform and saturated aqueous sodium hydrogen-carbonate. The organic layer was washed with brine and dried. The chloroform was removed and the residue was crystallized from n-hexane to give 2.39 g (yield: 77%) of the titled compound (II-2). This was recrystallized from ethyl acetate to give colorless crystals melting at 146°~148° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2.[CH:30]([B-](F)(F)F)=[CH2:31].[K+].C(N(CC)CC)C>C(O)C.OS([O-])(=O)=O.[K+]>[CH:30]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2)=[CH2:31]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (10.0 g, 21.3 mmol) in ethanol (200 mL) was added potassium vinyltrifluoroborate (4.28 g, 32 mmol) and triethylamine (4.5 mL, 32 mmol) followed by dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloromethane adduct (175 mg, 0.21 mmol). The reaction mixture was heated to reflux for 6 h, cooled to room temperature, diluted with 10% aqueous KHSO4 and the ethanol removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc and the organic phase washed with brine, dried over Na2SO4, solvent evaporated and crude product purified by chromatography on silica eluting with 40-60% EtOAc/hexane to give, after evaporation, the title compound (8.18 g). LRMS (ESI) m/z 417.2 [(M+H)+; calcd for C22H29N2O6: 417.2].
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][C:38](=[O:39])[O:40][CH3:41])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: COC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Yield: 11.2 %

Procedure:
Prepared using General Procedure 15: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (20.0 mg, 0.05 mmol) in DMF (1 mL) was added DIEA (19.4 mg, 0.15 mmol) and methyl chloroformate (9.5 mg, 0.1 mmol) for 4 h at room temperature. The solvent was evaporated and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC to afford 2.35 mg (11%) of (R)-methyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 149. LCMS-ESI (m/z) calculated for C23H22N4O4: 418.2. found 419.1 [M+H]+, tR=3.85 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.54-7.44 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.43-5.18 (m, 1H), 5.03 (d, J=8.6 Hz, 1H), 4.90-4.63 (m, 1H), 3.77 (d, J=27.4 Hz, 3H), 3.59-3.35 (m, 1H), 3.27-3.01 (m, 1H), 2.68 (ddd, J=12.7, 8.2, 4.7 Hz, 1H), 2.05-1.75 (m, 1H), 1.47 (t, J=5.6 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 167.82, 163.56, 157.51, 151.63, 139.77, 137.77, 128.85, 128.63, 123.19, 122.08, 121.53, 117.97, 111.55, 110.03, 108.32, 98.67, 51.00, 46.99, 28.68, 26.28, 24.46, 16.50.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36](=[O:37])[CH2:35][CH2:34][CH3:33])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. n-Butyryl chloride (0.3 g, 3.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2NHCl (30 mL). Solid was collected and slurried with ethanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-butyramide (0.5 g, 67%) as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 0.85 (t, J=7.4 Hz, 3H, CH3), 1.40-1.60 (m, 2H), 1.99-2.14 (m, 3H), 2.34-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.32-4.53 (m, 4H), 5.11-5.18 (dd, J=4.9 and 13.2 Hz, 1H, CH), 7.48-7.64 (m, 3H, Ar), 8.13 (t, J=5.1 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.67; 18.65, 22.61, 31.19, 37.16, 38.93, 46.15, 51.54, 121.62, 128.29, 130.60, 131.63, 134.82, 140.08, 168.08, 171.02, 172.01, 172.88; Anal. calcd. for C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 63.08; H, 6.06; N, 12.08.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=[CH:3]1.[Li]CCCC.[I:18]I.[NH4+].[Cl-]>C1COCC1>[I:18][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:4]=1
Reactant: II
Reactant: Cc1ccc(-c2cn(C)cn2)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(C)c(I)n2)s1
Temperature: -40 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A mixture of 1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 5 (2.36 g, 13.3 mmol) in THF (0.100 mL) was cooled −78° C. nBuLi (9.53 mL of a 1.6 M solution in hexanes, 15.2 mmol) was added dropwise (˜2 min) and the pale yellow solution was allowed to warm to −40° C. (over ˜1 h) and then re-cooled to −78° C. I2 (2.74 g, 10.4 mmol) was added and the mixture was allowed to warm to room temperature (over ˜2 h) and stirred overnight. Saturated aqueous NH4Cl (2 mL) was added and the mixture was concentrated to ˜10 mL. The mixture was diluted with CH2Cl2. H2O, saturated aqueous Na2S2O3 and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 25:75) to give 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (3.37 g, 84%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.46 (d, J=0.8 Hz, 3H), 3.59 (s, 3H), 6.62-6.66 (m, 1H), 7.04 (d, J=3.5 Hz, 1H), 7.11 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ15.3, 36.8, 91.0, 118.7, 122.2, 125.5, 134.3, 138.1, 140.5; HRMS (EI) m/z 303.9533 C9H9N21S [M]+. requires 303.9526.