Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[C:9]([O:11][C:12](=[O:14])[CH2:13]/1)=[O:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][NH:16]1>ClCCl>[CH:1](=[C:8](/[CH2:13][C:12]([N:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: O=C1C/C(=C\c2ccccc2)C(=O)O1
Solvent: ClCCl
Product: O=C(O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a suspension of (E)-benzylidenesuccinic anhydride (13.9 g) in dichloromethane (120 ml) was added cis-hexahydroisoindoline (12.0 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 1N hydrochloric acid and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 19.5 g of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.[C-:29]#[N:30].[Na+]>CS(C)=O.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:29]#[N:30])[CH2:5]1
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
trans-5-Methoxymethyl-3-tosyl-Cbz-pyrrolidine (3.55 g, 8.8 mmol) was dissolved in DMSO (8.8 mL). Finely ground NaCN(0.65 g, 13.2 mmol) was added, and the resulting reaction mixture was stirred 4 h at 80° C. The solution was cooled to room temperature, diluted with H2O (9 mL) and brine (9 mL), and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (2/1, v/v) to afford 2.09 g (87% yield) of the desired product as an oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:24])[CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH3:14].N1C=CC=CC=1>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH3:19])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:21]=1[CH3:22])=[O:24])[CH3:14]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
Similar to Example 1, m-nitrophenylhydrazine hydrochloride (10 mmol, 1.9 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a 50% solution of pyridine in ethanol. A precipitate was formed in the-reaction medium, and was collected by filtration. Analysis confirmed synthesis of the named product, m.p., 107.7° C.-109.2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:37]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of (3′-benzyloxybiphenyl-2yl)methanol from Step E (0.994 g, 3.42 mmol) and diphenylphosphoryl azide (1.13 g, 4.10 mmol) in dry toluene (6 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.62 g, 4.10 mmol) dropwise. The resulting mixture was stirred and allowed to warm to ambient temperature overnight. Toluene (6 mL) was added and the mixture was washed with water (2×5 mL), then 1.0 N aq. HCl (5 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 5% EtOAc in hexane, to give the titled product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12](=O)[N:11]2[CH:21]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:12]1[N:11]2[CH:21]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]2[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CCCC2
Product: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3

Procedure:
To 50 mL of POCl3 was added 2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (600 mg) and the resultant mixture was refluxed for 48 hours. The mixture was then cooled and the POCl3 was removed in vacuo. To the residue was added 20 mL of water and the pH adjusted to 7 with ammonium hydroxide. After cooling, the precipitated solid was collected to yield 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 30), m.p. 175°-176° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].CN(C)C1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: N#CC#N
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
15 g (81 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 200-ml four-necked flask. To the material was then added 121 ml (121 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen. The mixture was then stirred. To the mixture was then added 29.4 g (243 mmol) of N,N-dimethylaniline. The mixture was then heated at a temperature of 100° C. with stirring for 3 hours. N,N-dimethylaniline was then distilled off from the reaction mixture under a pressure of 30 mmHg. The reaction mixture was then allowed to cool to room temperature. 200 ml of water was then poured into the reaction mixture. The reaction mixture was acidified with hydrochloric acid, and a precipitate was recovered by filtration. The filtration residue was dissolved in 200 ml of a 5% aqueous solution of sodium hydroxide, and the solution was filtered. The filtrate was then acidified with hydrochloric acid. 2-Cyano-4-(p-tolyl)imidazole as a desired compound was then recovered by filtration. The material was then dried to obtain 12.43 g of a desired compound with a purity of 83.4% (yield: 70.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 85 %

Procedure:
4-Amino-phenol (12 g, 0.11 mol, Acros and Aldrich) was dissolved under an inert atmosphere, with stirring, in dry DMF (50 ml) and cooled in an ice-bath. Triethylamine (TEA, 11 g, 0.11 mol) was added and stirring continued for 1 hour. 4-Chloro-3-nitro-benzoyl chloride (22.2 g 0.1 mol, Acros and Aldrich) was added slowly and stirred overnight. The precipitated triethylamine.hydrochloride salt was filtered off and DMF removed under reduced pressure. The residue was extracted with EtOAc (3×100 ml) and citric acid (1M, 3×100 ml). The organic phase was dried with magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The title product was recrystallised from methanol/water (1:1, 250 ml), yield 85%, and analysed by NMR and MS.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([C:26]([NH:28][CH2:29][CH2:30]O)=[O:27])[N:23]([CH3:32])[C:22]=4[CH:33]=3)[C:14](=[O:34])[CH:13]=2)=[CH:8][CH:7]=1>C1COCC1>[O:27]1[CH2:30][CH2:29][N:28]=[C:26]1[C:24]1[N:23]([CH3:32])[C:22]2[CH:33]=[C:18]([N:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]4[CH:8]=[CH:7][C:6]([F:5])=[CH:36][CH:35]=4)=[CH:13][C:14]3=[O:34])[CH:19]=[CH:20][C:21]=2[N:25]=1
Reactant: Cn1c(C(=O)NCCO)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c(C2=NCCO2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
Thionyl chloride (0.078 ml) was added to a mixture of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-(2-hydroxyethyl)-1-methyl-1H-benzimidazole-2-carboxamide (50.0 mg) in THF (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h, and at 50° C. under Ar atmosphere for 2 h. After evaporation of the solvent, THF (2 ml) was added to the residue. NaH (40% oil dispersion, 34.3 mg) was added to the mixture at 0° C. The mixture was stirred at room temperature for 1 h, and at 50° C. under Ar atmosphere for 2 h. After addition of water (0.5 ml), the mixture was stirred at room temperature over weekend. The mixture was quenched with brine and extracted with EtOAc/THF. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was washed with EtOAc to give the title compound (17.9 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[C:17]3[CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:12]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(O)[C:11]=3[CH:10]=[CH:9][CH:8]=2)OCC[O:3]1.Cl>C(O)C>[C:2]([C:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[CH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: CN(C)CCCC1(O)c2ccccc2CCc2c(C3(C)OCCO3)cccc21
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cccc2c1CCc1ccccc1C2=CCCN(C)C

Procedure:
7.8 g. of 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated with 50 ml. of ethanol and 6 ml. of 25% ethanolic hydrochloric acid over a 21/2 hour period at reflux. Thereafter, the reaction mixture is concentrated under vacuum, dissolved in water, made alkaline with dilute sodium hydroxide and extracted with ether. The extract is washed with water, dried with sodium sulfate, filtered and evaporated whereby there is obtained 1-acetyl-10,11-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene as a yellow oil, whose NMR and IR spectrum are in agreement with their constitution. Through mass chromatography, it is determined that the product is a mixture of the geometric isomers α (30%) and β (70%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N.CC[N:20](CC)CC>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:20])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(S(N)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution 1-acetylindoline-5-sulfonyl chloride (Borror, A. L. et al., J. Org. Chem., 53:2047-2052 (1988)) (2.00 g, 7.70 mmol) in CH2Cl2 (5.0 mL) was added NH3 (38.5 mL, 19.3 mmol, 0.5M solution in dioxane) and Et3N (2.2 mL, 15.4 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo, and the residue was triturated with 1N aq. HCl solution (2×) and water (1×) to give the title compound (1.80 g, 97%) as a white solid. 1H NMR (DMSO-d6) δ 8.11 (d, J=8.1 Hz, 1H), 7.64-7.62 (m, 2H), 7.20 (br s, 2H), 4.16 (t, J=8.6 Hz, 2H), 3.19 (t, J=8.5 Hz, 2H), 2.19 (s, 3H); MS(ESI+) m/z 241.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1)=O.[I-].[CH:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2c(C)cccc2C=O)c1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: COC(=O)c1cccc(-c2c(C)cccc2CC(C)C)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 217 from methyl 2′-formyl-6′-methylbiphenyl-3-carboxylate and isopropyltriphenylphosphonium iodide. colorless oil (yield 45%).
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:17])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)cc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
Methyl iodide (3.42 ml, 7.81 g, 55 mmol) was added to a stirred mixture of N-(3-acetyl-4-hydroxyphenyl)acetamide (J.Org.Chem. 1995, 60, 4324-4330) (9.65 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) in dimethylformamide (50 ml). The mixture was stirred at room temperature for 72 hours, then the solvent was evaporated under reduced pressure. Water (100 ml) was added and the mixture was extracted with ethyl acetate (6×100 ml). The combined organic fractions were dried (MgSO4) and evaporated under reduced pressure to give N-(3-acetyl-4-methoxyphenyl)acetamide as a tan solid (10.34 g, 100%), 1H NMR (d6 -DMSO) δ 9.91 (1H, br. s), 7.76 (2H, m), 7.12 (1H, d, J=9.6 Hz), 3.86 (3H, s), 2.52 (3H, s), and 2.01 (3H, s). m/e (CI+) 208 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=O.O.NN.[OH-].[K+]>C(O)COCCO>[NH:14]1[C:15]2[C:11](=[C:10]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1ccccc1Cc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 22.74 g of the product of Step D of Example 3, 49.4 ml of hydrazine monohydrate, 96 ml of diethylene glycol and 38.4 ml of 38% caustic potassium hydroxide was stirred for 30 minutes at 140° C. and after the mixture was heated to 210° C., the water and hydrazine hydrate were distilled off. Stirring was continued for one hour at 210° C. and the mixture was allowed to return to ambient temperature and poured into 300 ml of a saturated aqueous soluton of sodium chloride. Extraction took place with ethyl acetate and the extracts were evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 20.55 g of the desired product melting at 139° C. which was used as is for the following step.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH:30]([CH3:32])[CH3:31])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH:30]([CH3:31])[CH3:32])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 6-fluoro-7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)3-methyl-nona-2E,4E,6E-trienoate (Compound 117, 86 mg, 0.20 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a light yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:19])=[N:8][S:9][C:10]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:4]([C:6]2[C:7]([CH3:19])=[N:8][S:9][C:10]=2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:5])=[CH:24][CH:23]=1
Reactant: CON(C)C(=O)c1c(C)nsc1NC(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)OC(C)(C)C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylisothiazol-5-ylcarbamate (1.20 g, 3.98 mmol) in THF (30 mL) at −10° C. was added a solution of (4-chlorophenyl)magnesium bromide (1 M in diethylether) (11.95 mL, 11.95 mmol). After a period of 15 min, additional Grignard reagent was added (11.95 mL). After a period of 30 min, the reaction mixture was quenched with saturated ammonium chloride and EtOAc. The organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (EtOAc/hexane 0:10 to 4:6) to give tert-butyl 4-(4-chlorobenzoyl)-3-methylisothiazol-5-ylcarbamate as an oil (1.1 g). LRMS (M+H)+: 353 m/z.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1.[C:13](#N)C.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>>[Br:1][C:2]1[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(NS(C)(=O)=O)n1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CN(c1nn(C)cc1Br)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Into a 8-dram vial, N-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-methanesulfonamide (1.38 g, 5.43 mmol), Acetonitrile (20 mL, 400 mmol), Potassium carbonate (1.50 g, 10.9 mmol), and Dimethyl sulfate (1.03 mL, 10.9 mmol) were added. The reaction mixture was heated at 50° C. overnight. The solid was filtered and washed DCM. The solvent was removed under vacuum to give a solid. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded N-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-N-methyl-methanesulfonamide as a white solid (1.20 (82%).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([CH3:8])[CH:6]=[CH2:7])([O-:3])=[O:2].[Na].[CH3:10][OH:11]>>[N+:1]([CH2:4][C:5]([CH3:8])=[CH:6][CH2:7][O:11][CH3:10])([O-:3])=[O:2]
Reactant: C=CC(C)=C[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COCC=C(C)C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
0.1 Mol of 1-nitro-2-methyl-1,3-butadiene was added to a solution of 0.1 Mol of sodium in methanol and stirred overnight. The reaction mixture was quenched in ice and extracted with methylene chloride. The oily residue was purified via column chromatography. The product was obtained as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccco1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Product: CC(CNCc1ccco1)Oc1ccc2ccccc2c1Cl
Yield: 56 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and furan-2-carbaldehyde in 56% yield as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].[O-:31][CH2:32][CH3:33].[Na+].O.Cl>CCO>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:31][CH2:32][CH3:33]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl
Yield: 80.8 %

Procedure:
A solution of 50 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 30 mg sodium ethoxide in 3 ml EtOH containing 5% of water was heated to 120° C. for 2 min using a microwave reactor. The reaction mixture was acidified to pH 4 with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 40 mg 2-{[1-(5-chloro-6-ethoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:15])([F:14])[C@@H:11]([OH:13])[CH3:12].CC([O-])(C)C.[K+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([O:13][C@@H:11]([CH3:12])[C:10]([F:15])([F:14])[F:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ncccc1Cl
Reactant: C[C@H](O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1ncccc1Cl)C(F)(F)F
Temperature: 60 °C
Yield: 64.5 %

Procedure:
To a solution of 3-chloro-2-fluoropyridine (115 mg, 0.88 mmol) and (25)-1,1,1-trifluoropropan-2-ol (45 wt % solution in TBME, 218 mg, 0.88 mmol) in THF (1 mL) was added potassium 2-methylpropan-2-olate (120 mg, 1.05 mmol) at room temperature under N2. The addition was slightly exothermic (˜40° C.). The resulting solution was warmed up to 60° C. for 10 minutes. The reaction mixture was diluted with water and extracted into DCM (3×5 mL) and the mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (128 mg, 65%) as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[CH:4]=[N:3]1.[Br:22][C:23]1[CH:24]=[N:25][C:26](I)=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:22][C:23]1[CH:24]=[N:25][C:26]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)=[N:27][CH:28]=1
Reactant: Cn1cc(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cn1
Reactant: Brc1cnc(I)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(-c3ncc(Br)cn3)c2)cn1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
To a solution of 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole (intermediate 1, 5.0 g, 17.5 mmol) in 1,4-dioxane (80 mL) was added 5-Bromo-2-iodo-pyrimidine (6.0 g, 21.0 mmol) and potassium carbonate (7.3 g, 5.25 mmol) in a sealed tube. The reaction mixture was purged with nitrogen for 30 min. Then Tetrakis(triphenyl phospine)Palladium(0) (2.02 g, 0.17 mmol) was added and the reaction mixture was heated at 100° C. O/N. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (EtOAc/hexane) afforded the title compound as a yellow solid (2.5 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.49 (t, J=1.64 Hz, 1H), 8.25 (s, 1H), 8.18 (dd, J=1.2, 4.74 Hz, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.75-7.73 (m, 1H), 7.52 (t, J=4.0 Hz, 1H), 3.88 (s, 3H). HPLC (Condition A): Rt 4.19 min (purity 98.9%). MS (ESI+): 317.0.